<clinical_study>
  <!-- This xml conforms to an XML Schema at:
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  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02208362</url>
  </required_header>
  <id_info>
    <org_study_id>13384</org_study_id>
    <secondary_id>NCI-2014-01488</secondary_id>
    <secondary_id>13384</secondary_id>
    <secondary_id>P30CA033572</secondary_id>
    <secondary_id>R01FD005129</secondary_id>
    <nct_id>NCT02208362</nct_id>
  </id_info>
  <brief_title>Genetically Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma</brief_title>
  <official_title>Phase I Study of Cellular ImmunoTx Using Memory Enriched T Cells Lentivirally Transduced to Express an IL13Rα2-Specific, Hinge-Optimized, 41BB-Costimulatory Chimeric Receptor and a Truncated CD19 for Pts With Rec/Ref MaligGlioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>City of Hope Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Food and Drug Administration (FDA)</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>City of Hope Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of genetically modified T-cell&#xD;
      immunotherapy in treating patients with malignant glioma that has come back (recurrent) or&#xD;
      has not responded to therapy (refractory). A T cell is a type of immune cell that can&#xD;
      recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and&#xD;
      a modified gene is placed into them in the laboratory and this may help them recognize and&#xD;
      kill glioma cells. Genetically modified T-cells may also help the body build an immune&#xD;
      response against the tumor cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded&#xD;
      autologous memory-enriched T cells that are genetically modified using a self-inactivating&#xD;
      (SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13R alpha&#xD;
      2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as&#xD;
      a truncated human cluster of differentiation 19 (CD19) for participants with&#xD;
      recurrent/refractory malignant glioma in one of the following ways: stratum 1 (intratumoral&#xD;
      delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ central memory T cells [Tcm]) (IL13R alpha&#xD;
      2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes),&#xD;
      stratum 2 (intracavitary delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm, stratum 3&#xD;
      (intraventricular delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm), stratum 4 (dual&#xD;
      delivery [both intratumoral and intraventricular] of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm),&#xD;
      or stratum 5 (dual delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ naive and memory T cells&#xD;
      [Tn/mem]).&#xD;
&#xD;
      II. To determine maximum tolerated dose schedule (MTD) and a recommended phase II dosing plan&#xD;
      (RP2D) for each stratum based on dose limiting toxicities (DLTs) and the full toxicity&#xD;
      profile.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the timing and extent of brain inflammation, as assessed by magnetic resonance&#xD;
      imaging (MRI)/magnetic resonance spectroscopy (MRS), following T cell administration.&#xD;
&#xD;
      II. To describe cytokine levels (cyst fluid, peripheral blood) over the study period.&#xD;
&#xD;
      III. In research participants who receive the full schedule of three CAR+ T cell doses IIIa.&#xD;
      Estimate the six month progression free survival rate. IIIb. Estimate disease response rates.&#xD;
      IIIc. Estimate median overall survival.&#xD;
&#xD;
      IV. In research participants who receive intraventricular infusions after progressing&#xD;
      following intratumoral/intracranial infusions (stratum 1 or 2):&#xD;
&#xD;
      IVa. Estimate disease response. IVb. Describe CAR T cell and endogenous immune populations,&#xD;
      as well as cytokine and microenvironment profiles (cerebral spinal fluid [CSF], cyst fluid,&#xD;
      peripheral blood) considering post progression therapy(ies), if applicable.&#xD;
&#xD;
      V. In research participants who receive at least one dose of CAR+ T cells estimate the mean&#xD;
      change from baseline in quality of life using the European Organization for Research and&#xD;
      Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and EORTC QLQ brain&#xD;
      neoplasm (BN)-20 survey scale, domain and item scores during and post treatment.&#xD;
&#xD;
      VI. For research participants who undergo a second resection or autopsy:&#xD;
&#xD;
      VIa. To evaluate CAR T cell persistence in the tumor micro-environment and the location of&#xD;
      the CAR T cells with respect to the injection.&#xD;
&#xD;
      VII. To evaluate IL13R alpha 2 antigen expression levels pre and post CAR T cell therapy.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 5 strata.&#xD;
&#xD;
      STRATUM I (Intratumoral delivery) CLOSED TO ACCRUAL 03/02/2018: Patients receive IL13R alpha&#xD;
      2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes&#xD;
      via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week&#xD;
      later, patients may receive additional T cell infusions as long as patients remain eligible&#xD;
      and there is product available. Patients who progress on intracavitary or intratumoral&#xD;
      administration may move to intraventricular catheter for the optional infusions.&#xD;
&#xD;
      STRATUM II (Intracavitary delivery): Patients receive IL13R alpha 2-specific,&#xD;
      hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via&#xD;
      intracavitary catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later,&#xD;
      patients may receive additional T cell infusions as long as patients continue to remain&#xD;
      eligible and there is product available. Patients who progress on intracavitary or&#xD;
      intratumoral administration may move to intraventricular catheter for the optional infusions.&#xD;
&#xD;
      STRATUM III (Intraventricular delivery): Patients receive IL13R alpha 2-specific,&#xD;
      hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via&#xD;
      intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week&#xD;
      later, patients may receive additional T cell infusions as long as patients continue to&#xD;
      remain eligible and there is product available.&#xD;
&#xD;
      STRATUM IV (Dual delivery): Patients receive IL13R alpha 2-specific, hinge-optimized,&#xD;
      41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and&#xD;
      intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week&#xD;
      later, patients may receive additional T cell infusions as long as patients continue to&#xD;
      remain eligible and there is product available. Based on clinical response after the first 3&#xD;
      infusions, the study principal investigator may decide to continue with the optional&#xD;
      infusions at either one or both sites (instead of requiring injections at both sites).&#xD;
&#xD;
      STRATUM V (Dual delivery): Patients receive IL13 [EQ]BBzeta/truncated CD19[t]+ Tn/mem via&#xD;
      intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks.&#xD;
      Beginning as early as 1 week later, patients may receive additional T cell infusions as long&#xD;
      as patients continue to remain eligible and there is product available. Based on clinical&#xD;
      response after the first 3 infusions, the study principal investigator may decide to continue&#xD;
      with the optional infusions at either one or both sites (instead of requiring injections at&#xD;
      both sites).&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10, and 12&#xD;
      months, and then yearly for 15 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 18, 2015</start_date>
  <completion_date type="Anticipated">December 18, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 18, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of grade 3 toxicity</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0, the revised cytokine release syndrome grading system as well as the modified neurological grading system.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of dose limiting toxicity (DLT), graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0</measure>
    <time_frame>Up to 1 week following the last course (not including optional courses 4-6)</time_frame>
    <description>Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval) will be estimated for participants' experiencing DLTs at the recommended phase II dosing plan schedule.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of toxicities, graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 as well as the modified neurological grading system</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and strata.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in largest length of tumor</measure>
    <time_frame>Baseline to up to 15 years</time_frame>
    <description>Descriptive statistics will be provided for brain inflammation (largest length of tumor) pre and post treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in cytokine levels</measure>
    <time_frame>Baseline to up to 6 weeks</time_frame>
    <description>Statistical and graphical methods will be used to describe the cytokine levels (cyst fluid, peripheral blood) over the study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in chimeric antigen receptor (CAR) T levels</measure>
    <time_frame>Baseline to up to 6 weeks</time_frame>
    <description>Statistical and graphical methods will be used to describe the CAR T cell levels (cyst fluid, peripheral blood) over the study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>From time of surgery assessed up to 15 years</time_frame>
    <description>Kaplan Meier methods will be used to estimate median PFS and graph the results.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease response by the Response Assessment in Neuro-Oncology criteria</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Estimated using 90% confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease response (stratum 1 and 2)</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Estimated using 90% confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CAR T cell detection (stratum 1 and 2)</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be detected peripheral blood and cerebral spinal fluid.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endogenous immune cell detection (stratum 1 and 2)</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be detected peripheral blood and cerebral spinal fluid.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cytokine and post progression therapy(ies) (stratum 1 and 2)</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be detected peripheral blood and cerebral spinal fluid.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>From time of surgery assessed up to 15 years</time_frame>
    <description>Kaplan Meier methods will be used to estimate median overall survival and graph the results. OS will also be examined for all patients, as well as, separately for those that received initial treatment only and those that received intraventricular infusion following progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in quality of life</measure>
    <time_frame>Baseline to up to 15 years</time_frame>
    <description>Estimate the mean and standard error for change from baseline during treatment and post treatment in the quality of life functioning scale, symptom scale and item scores from the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and the domain scale and items scores from the QLQ-brain neoplasm20.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T cell detection in tumor</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IL13Ra2 antigen expression levels</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">82</enrollment>
  <condition>Recurrent Glioblastoma</condition>
  <condition>Recurrent Malignant Glioma</condition>
  <condition>Recurrent WHO Grade II Glioma</condition>
  <condition>Recurrent WHO Grade III Glioma</condition>
  <condition>Refractory Glioblastoma</condition>
  <condition>Refractory Malignant Glioma</condition>
  <condition>Refractory WHO Grade II Glioma</condition>
  <condition>Refractory WHO Grade III Glioma</condition>
  <arm_group>
    <arm_group_label>Stratum I (T lymphocytes intratumoral)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CLOSED TO ACCRUAL 03/02/2018.&#xD;
Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum II (T lymphocytes intracavitary)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intracavitary catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum III (T lymphocytes intraventricular)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intraventricular catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum IV (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stratum V (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive IL13 [EQ]BBzeta/truncated CD19[t]+ Tn/mem via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells</intervention_name>
    <description>Given via intratumoral or intraventricular catheter</description>
    <arm_group_label>Stratum V (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <other_name>IL13 [EQ]BBzeta/truncated CD19[t]+ Naive and Memory T Cells</other_name>
    <other_name>IL13 [EQ]BBzeta/truncated CD19[t]+ TN/MEM Cells</other_name>
    <other_name>IL13Ra2-specific-hinge-optimized-4-1BB-CAR/truncated CD19-expressing Autologous TN/MEM Lymphocytes</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes</intervention_name>
    <description>Given via intratumoral, intracavitary, or intraventricular catheter</description>
    <arm_group_label>Stratum I (T lymphocytes intratumoral)</arm_group_label>
    <arm_group_label>Stratum II (T lymphocytes intracavitary)</arm_group_label>
    <arm_group_label>Stratum III (T lymphocytes intraventricular)</arm_group_label>
    <arm_group_label>Stratum IV (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <other_name>Autologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T Cells</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Stratum I (T lymphocytes intratumoral)</arm_group_label>
    <arm_group_label>Stratum II (T lymphocytes intracavitary)</arm_group_label>
    <arm_group_label>Stratum III (T lymphocytes intraventricular)</arm_group_label>
    <arm_group_label>Stratum IV (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <arm_group_label>Stratum V (T lymphocytes intratumoral and intraventricular)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Magnetic Resonance Imaging</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Stratum I (T lymphocytes intratumoral)</arm_group_label>
    <arm_group_label>Stratum II (T lymphocytes intracavitary)</arm_group_label>
    <arm_group_label>Stratum III (T lymphocytes intraventricular)</arm_group_label>
    <arm_group_label>Stratum IV (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <arm_group_label>Stratum V (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <other_name>Magnetic Resonance Imaging Scan</other_name>
    <other_name>Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance</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>Procedure</intervention_type>
    <intervention_name>Magnetic Resonance Spectroscopic Imaging</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Stratum I (T lymphocytes intratumoral)</arm_group_label>
    <arm_group_label>Stratum II (T lymphocytes intracavitary)</arm_group_label>
    <arm_group_label>Stratum III (T lymphocytes intraventricular)</arm_group_label>
    <arm_group_label>Stratum IV (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <arm_group_label>Stratum V (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <other_name>1H- Nuclear Magnetic Resonance Spectroscopic Imaging</other_name>
    <other_name>1H-nuclear magnetic resonance spectroscopic imaging</other_name>
    <other_name>Magnetic Resonance Spectroscopy</other_name>
    <other_name>MRS</other_name>
    <other_name>MRS Imaging</other_name>
    <other_name>MRSI</other_name>
    <other_name>Proton Magnetic Resonance Spectroscopic Imaging</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Quality-of-Life Assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Stratum I (T lymphocytes intratumoral)</arm_group_label>
    <arm_group_label>Stratum II (T lymphocytes intracavitary)</arm_group_label>
    <arm_group_label>Stratum III (T lymphocytes intraventricular)</arm_group_label>
    <arm_group_label>Stratum IV (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <arm_group_label>Stratum V (T lymphocytes intratumoral and intraventricular)</arm_group_label>
    <other_name>Quality of Life Assessment</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  SCREENING INCLUSION CRITERIA&#xD;
&#xD;
          -  Participant has a prior histologically-confirmed diagnosis of a grade III or IV&#xD;
             glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now&#xD;
             has radiographic progression consistent with a grade III or IV malignant glioma (MG)&#xD;
             after completing standard therapy&#xD;
&#xD;
          -  Radiographic evidence of progression/recurrence of the measurable disease more than 12&#xD;
             weeks after the end of the initial radiation therapy&#xD;
&#xD;
          -  Karnofsky performance status (KPS) &gt;= 60%&#xD;
&#xD;
          -  Life expectancy &gt; 4 weeks&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control or abstinence) prior to study entry and&#xD;
             for six months following duration of study participation; should a woman become&#xD;
             pregnant or suspect that she is pregnant while participating on the trial, she should&#xD;
             inform her treating physician immediately&#xD;
&#xD;
          -  City of Hope (COH) Clinical Pathology confirms IL13R alpha 2+ tumor expression by&#xD;
             immunohistochemistry (&gt;= 20%, 1+)&#xD;
&#xD;
          -  All research participants must have the ability to understand and the willingness to&#xD;
             sign a written informed consent&#xD;
&#xD;
          -  ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION&#xD;
&#xD;
          -  Research participant must not require more than 2 mg three times daily (TID) of&#xD;
             dexamethasone on the day of PBMC collection.&#xD;
&#xD;
          -  Research participant must have appropriate venous access&#xD;
&#xD;
          -  At least 2 weeks must have elapsed since the research participant received his/her&#xD;
             last dose of prior chemotherapy or radiation&#xD;
&#xD;
          -  ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT&#xD;
&#xD;
          -  Creatinine &lt; 1.6 mg/dL&#xD;
&#xD;
          -  White blood cell (WBC) &gt; 2,000/dl or&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt; 1,000&#xD;
&#xD;
          -  Platelets &gt;= 100,000/dl&#xD;
&#xD;
          -  International normalized ratio (INR) &lt; 1.3&#xD;
&#xD;
          -  Bilirubin &lt; 1.5 mg/dL&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &lt; 2.5 x upper&#xD;
             limits of normal&#xD;
&#xD;
          -  An interval of at least 12 weeks must have elapsed since the completion of initial&#xD;
             radiation therapy&#xD;
&#xD;
          -  Wash-out requirements (standard or investigational):&#xD;
&#xD;
               -  At least 6 weeks since the completion of a nitrosourea-containing chemotherapy&#xD;
                  regimen&#xD;
&#xD;
               -  At least 23 days since the completion of Temodar and/or 4 weeks for any other&#xD;
                  non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most&#xD;
                  recent treatment was with a targeted agent only, and s/he has recovered from any&#xD;
                  toxicity of this targeted agent, then a waiting period of only 2 weeks is needed&#xD;
                  from the last dose and the start of study treatment, with the exception of&#xD;
                  bevacizumab where a wash out period of at least 4 weeks is required before&#xD;
                  starting study treatment&#xD;
&#xD;
          -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH CAR T CELL INFUSION&#xD;
&#xD;
          -  Research participant has a released cryopreserved T cell product&#xD;
&#xD;
          -  Research participant does not require supplemental oxygen to keep saturation greater&#xD;
             than 95% and/or does not have presence of any radiographic abnormalities on chest&#xD;
             x-ray that are progressive&#xD;
&#xD;
          -  Research participant does not require pressor support and/or does not have symptomatic&#xD;
             cardiac arrhythmias&#xD;
&#xD;
          -  Research participant does not have a fever exceeding 38.5° Celsius (C); there is an&#xD;
             absence of positive blood cultures for bacteria, fungus, or virus within 48-hours&#xD;
             prior to T cell infusion and/or there aren't any indications of meningitis&#xD;
&#xD;
          -  Research participant serum total bilirubin does not exceed 2 x normal limit&#xD;
&#xD;
          -  Research participant transaminases does not exceed 2 x normal limit&#xD;
&#xD;
          -  Research participant serum creatinine =&lt; 1.8 mg/dL&#xD;
&#xD;
          -  Research participant does not have uncontrolled seizure activity following surgery&#xD;
             prior to starting the first T cell dose&#xD;
&#xD;
          -  Research participant platelet count must be &gt;= 100,000; however, if platelet level is&#xD;
             between 75,000-99,000, then T-cell infusion may proceed after platelet transfusion is&#xD;
             given and the post transfusion platelet count is &gt;= 100,000&#xD;
&#xD;
          -  Research participants must not require more than 2 mg TID of dexamethasone during T&#xD;
             cell therapy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  SCREENING EXCLUSION CRITERIA&#xD;
&#xD;
          -  Research participant requires supplemental oxygen to keep saturation greater than 95%&#xD;
             and the situation is not expected to resolve within 2 weeks&#xD;
&#xD;
          -  Research participant requires pressor support and/or has symptomatic cardiac&#xD;
             arrhythmias&#xD;
&#xD;
          -  Research participant requires dialysis&#xD;
&#xD;
          -  Research participant has uncontrolled seizure activity and/or clinically evident&#xD;
             progressive encephalopathy&#xD;
&#xD;
          -  Failure of research participant to understand the basic elements of the protocol&#xD;
             and/or the risks/benefits of participating in this phase I study; a legal guardian may&#xD;
             substitute for the research participant&#xD;
&#xD;
          -  Research participants with any non-malignant intercurrent illness which is either&#xD;
             poorly controlled with currently available treatment, or which is of such severity&#xD;
             that the investigators deem it unwise to enter the research participant on protocol&#xD;
             shall be ineligible&#xD;
&#xD;
          -  Research participants with any other active malignancies&#xD;
&#xD;
          -  Research participants being treated for severe infection or who are recovering from&#xD;
             major surgery are ineligible until recovery is deemed complete by the investigator&#xD;
&#xD;
          -  Research participants with any uncontrolled illness including ongoing or active&#xD;
             infection; research participants with known active hepatitis B or C infection;&#xD;
             research participants with any signs or symptoms of active infection, positive blood&#xD;
             cultures or radiological evidence of infections&#xD;
&#xD;
          -  Research participants who have confirmed human immunodeficiency virus (HIV) within 4&#xD;
             weeks of screening&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Behnam Badie</last_name>
    <role>Principal Investigator</role>
    <affiliation>City of Hope Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>City of Hope Comprehensive Cancer Center</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</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>August 1, 2014</study_first_submitted>
  <study_first_submitted_qc>August 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 5, 2014</study_first_posted>
  <last_update_submitted>July 3, 2023</last_update_submitted>
  <last_update_submitted_qc>July 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 5, 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>Glioblastoma</mesh_term>
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_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/NCT02208362
org study id: 13384
secondary id: NCI-2014-01488
secondary id: 13384
secondary id: P30CA033572
secondary id: R01FD005129
nct id: NCT02208362
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This phase I trial studies the side effects and best dose of genetically modified T-cell
      immunotherapy in treating patients with malignant glioma that has come back (recurrent) or
      has not responded to therapy (refractory). A T cell is a type of immune cell that can
      recognize and kill abnormal cells in the body. T cells are taken from the patient's blood and
      a modified gene is placed into them in the laboratory and this may help them recognize and
      kill glioma cells. Genetically modified T-cells may also help the body build an immune
      response against the tumor cells.
PRIMARY OBJECTIVES:

      I. To assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded
      autologous memory-enriched T cells that are genetically modified using a self-inactivating
      (SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13R alpha
      2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as
      a truncated human cluster of differentiation 19 (CD19) for participants with
      recurrent/refractory malignant glioma in one of the following ways: stratum 1 (intratumoral
      delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ central memory T cells [Tcm]) (IL13R alpha
      2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes),
      stratum 2 (intracavitary delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm, stratum 3
      (intraventricular delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm), stratum 4 (dual
      delivery [both intratumoral and intraventricular] of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm),
      or stratum 5 (dual delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ naive and memory T cells
      [Tn/mem]).

      II. To determine maximum tolerated dose schedule (MTD) and a recommended phase II dosing plan
      (RP2D) for each stratum based on dose limiting toxicities (DLTs) and the full toxicity
      profile.

      SECONDARY OBJECTIVES:

      I. To assess the timing and extent of brain inflammation, as assessed by magnetic resonance
      imaging (MRI)/magnetic resonance spectroscopy (MRS), following T cell administration.

      II. To describe cytokine levels (cyst fluid, peripheral blood) over the study period.

      III. In research participants who receive the full schedule of three CAR+ T cell doses IIIa.
      Estimate the six month progression free survival rate. IIIb. Estimate disease response rates.
      IIIc. Estimate median overall survival.

      IV. In research participants who receive intraventricular infusions after progressing
      following intratumoral/intracranial infusions (stratum 1 or 2):

      IVa. Estimate disease response. IVb. Describe CAR T cell and endogenous immune populations,
      as well as cytokine and microenvironment profiles (cerebral spinal fluid [CSF], cyst fluid,
      peripheral blood) considering post progression therapy(ies), if applicable.

      V. In research participants who receive at least one dose of CAR+ T cells estimate the mean
      change from baseline in quality of life using the European Organization for Research and
      Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and EORTC QLQ brain
      neoplasm (BN)-20 survey scale, domain and item scores during and post treatment.

      VI. For research participants who undergo a second resection or autopsy:

      VIa. To evaluate CAR T cell persistence in the tumor micro-environment and the location of
      the CAR T cells with respect to the injection.

      VII. To evaluate IL13R alpha 2 antigen expression levels pre and post CAR T cell therapy.

      OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 5 strata.

      STRATUM I (Intratumoral delivery) CLOSED TO ACCRUAL 03/02/2018: Patients receive IL13R alpha
      2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes
      via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
      later, patients may receive additional T cell infusions as long as patients remain eligible
      and there is product available. Patients who progress on intracavitary or intratumoral
      administration may move to intraventricular catheter for the optional infusions.

      STRATUM II (Intracavitary delivery): Patients receive IL13R alpha 2-specific,
      hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via
      intracavitary catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later,
      patients may receive additional T cell infusions as long as patients continue to remain
      eligible and there is product available. Patients who progress on intracavitary or
      intratumoral administration may move to intraventricular catheter for the optional infusions.

      STRATUM III (Intraventricular delivery): Patients receive IL13R alpha 2-specific,
      hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via
      intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
      later, patients may receive additional T cell infusions as long as patients continue to
      remain eligible and there is product available.

      STRATUM IV (Dual delivery): Patients receive IL13R alpha 2-specific, hinge-optimized,
      41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and
      intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
      later, patients may receive additional T cell infusions as long as patients continue to
      remain eligible and there is product available. Based on clinical response after the first 3
      infusions, the study principal investigator may decide to continue with the optional
      infusions at either one or both sites (instead of requiring injections at both sites).

      STRATUM V (Dual delivery): Patients receive IL13 [EQ]BBzeta/truncated CD19[t]+ Tn/mem via
      intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks.
      Beginning as early as 1 week later, patients may receive additional T cell infusions as long
      as patients continue to remain eligible and there is product available. Based on clinical
      response after the first 3 infusions, the study principal investigator may decide to continue
      with the optional infusions at either one or both sites (instead of requiring injections at
      both sites).

      After completion of study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10, and 12
      months, and then yearly for 15 years.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of grade 3 toxicity
time frame: Up to 15 years
description: Will be graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0, the revised cytokine release syndrome grading system as well as the modified neurological grading system.
measure: Incidence of dose limiting toxicity (DLT), graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
time frame: Up to 1 week following the last course (not including optional courses 4-6)
description: Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval) will be estimated for participants' experiencing DLTs at the recommended phase II dosing plan schedule.
measure: Incidence of toxicities, graded using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 as well as the modified neurological grading system
time frame: Up to 15 years
description: Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and strata.
measure: Changes in largest length of tumor
time frame: Baseline to up to 15 years
description: Descriptive statistics will be provided for brain inflammation (largest length of tumor) pre and post treatment.
measure: Changes in cytokine levels
time frame: Baseline to up to 6 weeks
description: Statistical and graphical methods will be used to describe the cytokine levels (cyst fluid, peripheral blood) over the study period.
measure: Changes in chimeric antigen receptor (CAR) T levels
time frame: Baseline to up to 6 weeks
description: Statistical and graphical methods will be used to describe the CAR T cell levels (cyst fluid, peripheral blood) over the study period.
measure: Progression free survival (PFS)
time frame: From time of surgery assessed up to 15 years
description: Kaplan Meier methods will be used to estimate median PFS and graph the results.
measure: Disease response by the Response Assessment in Neuro-Oncology criteria
time frame: Up to 15 years
description: Estimated using 90% confidence interval.
measure: Disease response (stratum 1 and 2)
time frame: Up to 15 years
description: Estimated using 90% confidence interval.
measure: CAR T cell detection (stratum 1 and 2)
time frame: Up to 15 years
description: Will be detected peripheral blood and cerebral spinal fluid.
measure: Endogenous immune cell detection (stratum 1 and 2)
time frame: Up to 15 years
description: Will be detected peripheral blood and cerebral spinal fluid.
measure: Cytokine and post progression therapy(ies) (stratum 1 and 2)
time frame: Up to 15 years
description: Will be detected peripheral blood and cerebral spinal fluid.
measure: Overall survival (OS)
time frame: From time of surgery assessed up to 15 years
description: Kaplan Meier methods will be used to estimate median overall survival and graph the results. OS will also be examined for all patients, as well as, separately for those that received initial treatment only and those that received intraventricular infusion following progression.
measure: Changes in quality of life
time frame: Baseline to up to 15 years
description: Estimate the mean and standard error for change from baseline during treatment and post treatment in the quality of life functioning scale, symptom scale and item scores from the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and the domain scale and items scores from the QLQ-brain neoplasm20.
measure: T cell detection in tumor
time frame: Up to 1 year
description: In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.
measure: IL13Ra2 antigen expression levels
time frame: Up to 1 year
description: In study participants that undergo a second resection or following autopsy, T cells numbers, location, and antigen levels will be described.
arm group label: Stratum I (T lymphocytes intratumoral)
arm group type: Experimental
description: CLOSED TO ACCRUAL 03/02/2018.
Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions.
arm group label: Stratum II (T lymphocytes intracavitary)
arm group type: Experimental
description: Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intracavitary catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to intraventricular catheter for the optional infusions
arm group label: Stratum III (T lymphocytes intraventricular)
arm group type: Experimental
description: Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intraventricular catheter over 5-10 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available.
arm group label: Stratum IV (T lymphocytes intratumoral and intraventricular)
arm group type: Experimental
description: Patients receive IL13R alpha 2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).
arm group label: Stratum V (T lymphocytes intratumoral and intraventricular)
arm group type: Experimental
description: Patients receive IL13 [EQ]BBzeta/truncated CD19[t]+ Tn/mem via intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later, patients may receive additional T cell infusions as long as patients continue to remain eligible and there is product available. Based on clinical response after the first 3 infusions, the study principal investigator may decide to continue with the optional infusions at either one or both sites (instead of requiring injections at both sites).
intervention type: Biological
intervention name: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
description: Given via intratumoral or intraventricular catheter
arm group label: Stratum V (T lymphocytes intratumoral and intraventricular)
other name: IL13 [EQ]BBzeta/truncated CD19[t]+ Naive and Memory T Cells
other name: IL13 [EQ]BBzeta/truncated CD19[t]+ TN/MEM Cells
other name: IL13Ra2-specific-hinge-optimized-4-1BB-CAR/truncated CD19-expressing Autologous TN/MEM Lymphocytes
intervention type: Biological
intervention name: IL13Ralpha2-specific Hinge-optimized 41BB-co-stimulatory CAR Truncated CD19-expressing Autologous T-Lymphocytes
description: Given via intratumoral, intracavitary, or intraventricular catheter
arm group label: Stratum I (T lymphocytes intratumoral)
arm group label: Stratum II (T lymphocytes intracavitary)
arm group label: Stratum III (T lymphocytes intraventricular)
arm group label: Stratum IV (T lymphocytes intratumoral and intraventricular)
other name: Autologous IL13(EQ)BBzeta/CD19t+ TCM-enriched T Cells
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Stratum I (T lymphocytes intratumoral)
arm group label: Stratum II (T lymphocytes intracavitary)
arm group label: Stratum III (T lymphocytes intraventricular)
arm group label: Stratum IV (T lymphocytes intratumoral and intraventricular)
arm group label: Stratum V (T lymphocytes intratumoral and intraventricular)
intervention type: Procedure
intervention name: Magnetic Resonance Imaging
description: Correlative studies
arm group label: Stratum I (T lymphocytes intratumoral)
arm group label: Stratum II (T lymphocytes intracavitary)
arm group label: Stratum III (T lymphocytes intraventricular)
arm group label: Stratum IV (T lymphocytes intratumoral and intraventricular)
arm group label: Stratum V (T lymphocytes intratumoral and intraventricular)
other name: Magnetic Resonance Imaging Scan
other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
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: Procedure
intervention name: Magnetic Resonance Spectroscopic Imaging
description: Correlative studies
arm group label: Stratum I (T lymphocytes intratumoral)
arm group label: Stratum II (T lymphocytes intracavitary)
arm group label: Stratum III (T lymphocytes intraventricular)
arm group label: Stratum IV (T lymphocytes intratumoral and intraventricular)
arm group label: Stratum V (T lymphocytes intratumoral and intraventricular)
other name: 1H- Nuclear Magnetic Resonance Spectroscopic Imaging
other name: 1H-nuclear magnetic resonance spectroscopic imaging
other name: Magnetic Resonance Spectroscopy
other name: MRS
other name: MRS Imaging
other name: MRSI
other name: Proton Magnetic Resonance Spectroscopic Imaging
intervention type: Other
intervention name: Quality-of-Life Assessment
description: Ancillary studies
arm group label: Stratum I (T lymphocytes intratumoral)
arm group label: Stratum II (T lymphocytes intracavitary)
arm group label: Stratum III (T lymphocytes intraventricular)
arm group label: Stratum IV (T lymphocytes intratumoral and intraventricular)
arm group label: Stratum V (T lymphocytes intratumoral and intraventricular)
other name: Quality of Life Assessment
criteria: 
gender: All
minimum age: 12 Years
maximum age: 75 Years
healthy volunteers: No
last name: Behnam Badie
role: Principal Investigator
affiliation: City of Hope Medical Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Glioma
mesh term: Recurrence