<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/NCT03283631</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00083828</org_study_id>
    <secondary_id>5P50CA190991-03</secondary_id>
    <nct_id>NCT03283631</nct_id>
  </id_info>
  <brief_title>Intracerebral EGFR-vIII CAR-T Cells for Recurrent GBM</brief_title>
  <acronym>INTERCEPT</acronym>
  <official_title>INTERCEPT: INTracerebral EGFR-vIII Chimeric Antigen Receptor Gene-Modified T CElls for PaTients With Recurrent GBM</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gary Archer Ph.D.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Duke Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</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>
      The goal of this protocol is to transfer autologous peripheral blood mononuclear cells&#xD;
      (PBMCs) transduced with genes encoding a chimeric antigen receptor (CAR) that recognizes&#xD;
      epidermal growth factor receptor variant III (EGFRvIII) tumor-specific antigen into patients&#xD;
      with recurrent glioblastoma (GBM) following stereotactic radiosurgery (SRS). The CAR used is&#xD;
      targeted to a tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII,&#xD;
      which is expressed on a subset of patients. Normal PBMCs derived from patients with GBM are&#xD;
      genetically engineered with a viral vector encoding the CAR and infused directly into the&#xD;
      patient's tumor with the aim of mediating regression of their tumors. Despite our CAR being&#xD;
      targeted to a tumor specific antigen, given the prior toxicity using CARs that were not&#xD;
      targeted to tumor-specific antigens, the investigators elected to begin with very low doses&#xD;
      of cells. Enrollment on this study was suspended in April 2020 while an amendment to reduce&#xD;
      the anticipated number of participants was under review and approved. The decision to&#xD;
      terminate the study was made in January, 2021 to shift toward the next iteration of a related&#xD;
      CAR T cell trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with evidence of radiographic recurrence who expressed EGFRvIII on their original&#xD;
      tumor diagnosis had autologous PBMCs harvested by leukapheresis. These autologous PBMCs were&#xD;
      transduced with a retrovirus containing the sequences for the EGFRvIII CAR and sent to the&#xD;
      Duke Radiopharmacy for radiolabeling with 111Indium (111In). Within 2-3 weeks of&#xD;
      leukapheresis, on Day -4 to -2, patients had a BrainLab MRI to prepare for biopsy and&#xD;
      catheter placement. On Day -1, the patient underwent standard of care (SOC) stereotactic&#xD;
      biopsy under local anesthesia to confirm tumor recurrence. At the time of biopsy, prior to&#xD;
      catheter insertion and administration of study drug, the presence of recurrent tumor was&#xD;
      confirmed by histopathology. If tumor recurrence was confirmed, a catheter was placed&#xD;
      intratumorally for delivery of EGFRvIII-CARs by Convection Enhanced Delivery (CED).&#xD;
&#xD;
      SRS will took place on Day 0 (+1 day) and 111In-labeled EGFRvIII-CARs were infused on the&#xD;
      same day over a 6 to 6.5 hour period immediately after SRS.&#xD;
&#xD;
      On days 1 and 2 after 111In-labeled EGFRvIII-CAR infusion, whole planar imaging followed by&#xD;
      Single-Photon Emission Computed Tomography (SPECT) Computed Tomography (CT) imaging assessed&#xD;
      the intracerebral and systemic localization of the 111In-labeled EGFRvIII-CARs that described&#xD;
      the distribution of EGFRvIII-CARs within the brain and systemically.&#xD;
&#xD;
      This protocol was designed to determine the maximum tolerated dose (MTD) of a novel,&#xD;
      tumor-specific treatment with autologous EGFRvIII-CARs. The proposed starting dose was 2.5 x&#xD;
      10^8 of 111In-labeled cells in 3 milliliters (mL). The infusion flow rate was fixed at 0.5&#xD;
      mL/hr.&#xD;
&#xD;
      Enrollment on this study was suspended in April 2020 while an amendment to reduce the&#xD;
      anticipated number of participants was under review and approved. Upon approval of this&#xD;
      amendment, the enrollment suspension remained due to a change in access to necessary&#xD;
      equipment for CAR manufacturing. The decision to terminate the study was made in January,&#xD;
      2021 to shift toward the next iteration of a related CAR T cell trial. The knowledge gained&#xD;
      from this study experience is directing our next CAR T-cell platform and will be used to&#xD;
      secure additional funding.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    We are halting enrollment of this study.&#xD;
  </why_stopped>
  <start_date type="Actual">May 30, 2018</start_date>
  <completion_date type="Actual">June 30, 2020</completion_date>
  <primary_completion_date type="Actual">September 19, 2019</primary_completion_date>
  <phase>Phase 1</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>Determination of Maximum Tolerated Dose (MTD)</measure>
    <time_frame>4 weeks</time_frame>
    <description>MTD of EGFRvIII-CAR gene-modified T cells when administered intracerebrally by CED after SRS in patients with recurrent GBM</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of T Cell trafficking within the brain tumor</measure>
    <time_frame>2 days</time_frame>
    <description>Change in volume of distribution and maximal percentage of enhanced tumor volume covered</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of T cell trafficking systemically</measure>
    <time_frame>2 days</time_frame>
    <description>Change in the volume of distribution of 111In-labeled EGFRvIII-CARs present in each body area (neck, chest, abdomen, pelvis, and extremities)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median survival</measure>
    <time_frame>1 year</time_frame>
    <description>The time between SRS / CAR treatment and death or last follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median progression-free survival</measure>
    <time_frame>1 year</time_frame>
    <description>The time between SRS / CAR treatment and first failure (death or disease progression)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Recurrent Glioblastoma</condition>
  <condition>Recurrent Gliosarcoma</condition>
  <arm_group>
    <arm_group_label>EGFRvIII-CARs</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>EGFRvIII-CARs</intervention_name>
    <description>Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells</description>
    <arm_group_label>EGFRvIII-CARs</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Disease progression or recurrence of a supratentorial World Health Organization (WHO)&#xD;
             grade IV malignant glioma (GBM or gliosarcoma) based on imaging studies with&#xD;
             measurable disease. At the time of biopsy, prior to stereotactic radiosurgery (SRS)&#xD;
             and administration of the EGFRvIII-CARS, the presence of recurrent tumor must be&#xD;
             confirmed by histopathological analysis.&#xD;
&#xD;
          2. Adults ≥ 18 years old.&#xD;
&#xD;
          3. Karnofsky Performance Status (KPS) score ≥ 70.&#xD;
&#xD;
          4. EGFRvIII, the target antigen, must be identified on tumor tissue by&#xD;
             immunohistochemistry (IHC) or Polymerase Chain Reaction (PCR), i.e. EGFRvIII positive&#xD;
             via pathology report.&#xD;
&#xD;
          5. Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,000 cells/µl, platelets ≥&#xD;
             125,000 cells/µl (prior to biopsy).&#xD;
&#xD;
          6. Serum creatinine ≤ 1.5 mg/dl, serum glutamic oxaloacetic transaminase (SGOT), and&#xD;
             bilirubin ≤ 1.5 times upper limit of normal (prior to biopsy).&#xD;
&#xD;
          7. Signed informed consent approved by the Institutional Review Board.&#xD;
&#xD;
          8. Female patients must not be pregnant or breast-feeding. Female patients of&#xD;
             childbearing potential (defined as &lt; 2 years after last menstruation or not surgically&#xD;
             sterile) must use a highly effective contraceptive method (allowed methods of birth&#xD;
             control, [i.e. with a failure rate of &lt; 1% per year] are implants, injectables,&#xD;
             combined oral contraceptives, intra-uterine device [IUD; only hormonal], sexual&#xD;
             abstinence or vasectomized partner) during the trial and for a period of &gt; 6 months&#xD;
             following the last administration of trial drug(s). Female patients with an intact&#xD;
             uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy&#xD;
             test within 48 hours prior to starting SRS.&#xD;
&#xD;
          9. Fertile male patients must agree to use a highly effective contraceptive method&#xD;
             (allowed methods of birth control [i.e. with a failure rate of &lt; 1% per year] include&#xD;
             a female partner using implants, injectables, combined oral contraceptives, IUDs [only&#xD;
             hormonal], sexual abstinence or prior vasectomy) during the trial and for a period of&#xD;
             &gt; 6 months following the last administration of trial drugs.&#xD;
&#xD;
         10. Meet eligibility requirements for SRS: able to get MRI; the patient must have a lesion&#xD;
             that, in the opinion of the study radiation oncologist, can safely receive SRS to the&#xD;
             entire tumor; must not be abutting optic apparatus or brainstem and catheter tip will&#xD;
             be at least 5mm away from the ventricle; and must be able to be secured and positioned&#xD;
             in a stereotactic U-frame mask.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant or breast-feeding.&#xD;
&#xD;
          2. Patients with known potentially anaphylactic allergic reactions to gadolinium-DTPA.&#xD;
&#xD;
          3. Patients who cannot undergo MRI with contrast or SPECT/CT.&#xD;
&#xD;
          4. Patients with evidence of tumor in the brainstem, cerebellum, optic apparatus, or&#xD;
             spinal cord, radiological evidence of actively growing multifocal disease, or&#xD;
             leptomeningeal disease.&#xD;
&#xD;
          5. Patients &lt; 12 weeks from the end of radiation therapy, unless they have two&#xD;
             progressive scans at least 4 weeks apart, have progression outside of the radiation&#xD;
             field, or have histologic confirmation of progression.&#xD;
&#xD;
          6. Severe, active comorbidity, including any of the following:&#xD;
&#xD;
               1. Unstable angina and/or congestive heart failure requiring hospitalization;&#xD;
&#xD;
               2. Transmural myocardial infarction within the last 6 months;&#xD;
&#xD;
               3. Acute bacterial or fungal infection requiring intravenous antibiotics at the time&#xD;
                  of study initiation;&#xD;
&#xD;
               4. Chronic obstructive pulmonary disease exacerbation or other respiratory illness&#xD;
                  requiring hospitalization or precluding study therapy;&#xD;
&#xD;
               5. Known hepatic insufficiency resulting in clinical jaundice and/or coagulation&#xD;
                  defects;&#xD;
&#xD;
               6. Known autoimmune disorder, such as HIV;&#xD;
&#xD;
               7. Major medical illnesses or psychiatric impairments that, in the investigator's&#xD;
                  opinion, will prevent administration or completion of protocol therapy;&#xD;
&#xD;
               8. Active connective tissue disorders, such as lupus or scleroderma that, in the&#xD;
                  opinion of the treating physician, may put the patient at high risk for radiation&#xD;
                  toxicity.&#xD;
&#xD;
          7. Co-medication that may interfere with study results; e.g. immuno-suppressive agents&#xD;
             other than corticosteroids.&#xD;
&#xD;
          8. Prior, unrelated malignancy requiring current active treatment with the exception of&#xD;
             cervical carcinoma in situ and adequately treated basal cell or squamous cell&#xD;
             carcinoma of the skin;&#xD;
&#xD;
          9. Current, recent (within 4 weeks of the administration of this study agent), or planned&#xD;
             participation in another experimental therapeutic drug study.&#xD;
&#xD;
         10. Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except for&#xD;
             nitrosourea (6 weeks) or metronomic dosed chemotherapy such as daily etoposide or&#xD;
             cyclophosphamide (1 week)] prior to biopsy unless patients have recovered from side&#xD;
             effects of such therapy.&#xD;
&#xD;
         11. Patients with an active infection requiring intravenous treatment or having an&#xD;
             unexplained febrile illness (Tmax &gt; 99.5 F, 37.5 C).&#xD;
&#xD;
         12. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to CAR&#xD;
             T Cell infusion.&#xD;
&#xD;
         13. Prior therapy targeted to EGFRvIII.&#xD;
&#xD;
         14. Prior history of brain SRS, (patients who have received external beam radiation per&#xD;
             standard of care are allowed).&#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>Daniel Landi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>David Ashley, MBBS, FRACP, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://tischbraintumorcenter.duke.edu/</url>
    <description>The Preston Robert Tisch Brain Tumor Center</description>
  </link>
  <link>
    <url>http://www.dukecancerinstitute.org/clinical-trials</url>
    <description>Duke Cancer Institute</description>
  </link>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>September 13, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <last_update_submitted>April 1, 2021</last_update_submitted>
  <last_update_submitted_qc>April 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Duke University</investigator_affiliation>
    <investigator_full_name>Gary Archer Ph.D.</investigator_full_name>
    <investigator_title>Assistant Professor of Neurosurgery</investigator_title>
  </responsible_party>
  <keyword>Malignant Glioma</keyword>
  <keyword>INTERCEPT</keyword>
  <keyword>Pro00083828</keyword>
  <keyword>Adult</keyword>
  <keyword>Chimeric Antigen Receptor</keyword>
  <keyword>CAR T cell</keyword>
  <keyword>EGFRvIII</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Gliosarcoma</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/NCT03283631
org study id: Pro00083828
secondary id: 5P50CA190991-03
nct id: NCT03283631
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The goal of this protocol is to transfer autologous peripheral blood mononuclear cells
      (PBMCs) transduced with genes encoding a chimeric antigen receptor (CAR) that recognizes
      epidermal growth factor receptor variant III (EGFRvIII) tumor-specific antigen into patients
      with recurrent glioblastoma (GBM) following stereotactic radiosurgery (SRS). The CAR used is
      targeted to a tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII,
      which is expressed on a subset of patients. Normal PBMCs derived from patients with GBM are
      genetically engineered with a viral vector encoding the CAR and infused directly into the
      patient's tumor with the aim of mediating regression of their tumors. Despite our CAR being
      targeted to a tumor specific antigen, given the prior toxicity using CARs that were not
      targeted to tumor-specific antigens, the investigators elected to begin with very low doses
      of cells. Enrollment on this study was suspended in April 2020 while an amendment to reduce
      the anticipated number of participants was under review and approved. The decision to
      terminate the study was made in January, 2021 to shift toward the next iteration of a related
      CAR T cell trial.
Patients with evidence of radiographic recurrence who expressed EGFRvIII on their original
      tumor diagnosis had autologous PBMCs harvested by leukapheresis. These autologous PBMCs were
      transduced with a retrovirus containing the sequences for the EGFRvIII CAR and sent to the
      Duke Radiopharmacy for radiolabeling with 111Indium (111In). Within 2-3 weeks of
      leukapheresis, on Day -4 to -2, patients had a BrainLab MRI to prepare for biopsy and
      catheter placement. On Day -1, the patient underwent standard of care (SOC) stereotactic
      biopsy under local anesthesia to confirm tumor recurrence. At the time of biopsy, prior to
      catheter insertion and administration of study drug, the presence of recurrent tumor was
      confirmed by histopathology. If tumor recurrence was confirmed, a catheter was placed
      intratumorally for delivery of EGFRvIII-CARs by Convection Enhanced Delivery (CED).

      SRS will took place on Day 0 (+1 day) and 111In-labeled EGFRvIII-CARs were infused on the
      same day over a 6 to 6.5 hour period immediately after SRS.

      On days 1 and 2 after 111In-labeled EGFRvIII-CAR infusion, whole planar imaging followed by
      Single-Photon Emission Computed Tomography (SPECT) Computed Tomography (CT) imaging assessed
      the intracerebral and systemic localization of the 111In-labeled EGFRvIII-CARs that described
      the distribution of EGFRvIII-CARs within the brain and systemically.

      This protocol was designed to determine the maximum tolerated dose (MTD) of a novel,
      tumor-specific treatment with autologous EGFRvIII-CARs. The proposed starting dose was 2.5 x
      10^8 of 111In-labeled cells in 3 milliliters (mL). The infusion flow rate was fixed at 0.5
      mL/hr.

      Enrollment on this study was suspended in April 2020 while an amendment to reduce the
      anticipated number of participants was under review and approved. Upon approval of this
      amendment, the enrollment suspension remained due to a change in access to necessary
      equipment for CAR manufacturing. The decision to terminate the study was made in January,
      2021 to shift toward the next iteration of a related CAR T cell trial. The knowledge gained
      from this study experience is directing our next CAR T-cell platform and will be used to
      secure additional funding.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Determination of Maximum Tolerated Dose (MTD)
time frame: 4 weeks
description: MTD of EGFRvIII-CAR gene-modified T cells when administered intracerebrally by CED after SRS in patients with recurrent GBM
measure: Assessment of T Cell trafficking within the brain tumor
time frame: 2 days
description: Change in volume of distribution and maximal percentage of enhanced tumor volume covered
measure: Assessment of T cell trafficking systemically
time frame: 2 days
description: Change in the volume of distribution of 111In-labeled EGFRvIII-CARs present in each body area (neck, chest, abdomen, pelvis, and extremities)
measure: Median survival
time frame: 1 year
description: The time between SRS / CAR treatment and death or last follow-up
measure: Median progression-free survival
time frame: 1 year
description: The time between SRS / CAR treatment and first failure (death or disease progression)
arm group label: EGFRvIII-CARs
arm group type: Experimental
description: Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells
intervention type: Biological
intervention name: EGFRvIII-CARs
description: Gamma-retroviral MSGV1 139 scFv EGFRvIII CAR gene-modified T cells
arm group label: EGFRvIII-CARs
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Daniel Landi, MD
role: Principal Investigator
affiliation: Duke University
last name: David Ashley, MBBS, FRACP, PhD
role: Principal Investigator
affiliation: Duke University
facility: 
country: United States
url: https://tischbraintumorcenter.duke.edu/
description: The Preston Robert Tisch Brain Tumor Center
url: http://www.dukecancerinstitute.org/clinical-trials
description: Duke Cancer Institute
responsible party type: Sponsor-Investigator
investigator affiliation: Duke University
investigator full name: Gary Archer Ph.D.
investigator title: Assistant Professor of Neurosurgery
mesh term: Glioblastoma
mesh term: Gliosarcoma
mesh term: Recurrence