<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/NCT02209376</url>
  </required_header>
  <id_info>
    <org_study_id>UPCC 35313, 820381</org_study_id>
    <nct_id>NCT02209376</nct_id>
  </id_info>
  <brief_title>Autologous T Cells Redirected to EGFRVIII-With a Chimeric Antigen Receptor in Patients With EGFRVIII+ Glioblastoma</brief_title>
  <official_title>Pilot Study of Autologous T Cells Redirected to EGFRVIII-With a Chimeric Antigen Receptor in Patients With EGFRVIII+ Glioblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pennsylvania</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      An Open-Label Phase 1 Pilot Study to determine the safety and feasibility of CART-EGFRvIII&#xD;
      (autologous T cells transduced with a lentiviral vector to express a chimeric antigen&#xD;
      receptor specific for EGFRvIII) in the treatment of patients with EGFRvIII+ glioblastoma who&#xD;
      have had their first recurrence as determined by standard imaging or have have residual&#xD;
      disease after initial resection.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Sponsor decision to terminate prior to completion to pursue combination therapies.&#xD;
  </why_stopped>
  <start_date type="Actual">November 18, 2014</start_date>
  <completion_date type="Actual">April 4, 2018</completion_date>
  <primary_completion_date type="Actual">April 4, 2018</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>Number of adverse events</measure>
    <time_frame>2 years</time_frame>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">11</enrollment>
  <condition>Patients With Residual or Reccurent EGFRvIII+ Glioma</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CART-EGFRvIII T cells</intervention_name>
    <arm_group_label>Arm 1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pathological criteria: Glioblastoma (GBM) that is histologically confirmed by&#xD;
             pathology review of surgically resected tissue.&#xD;
&#xD;
          -  Tumor cells from resected tissue must be available for EGFRvIII testing. Patients who&#xD;
             have previously been treated with an EGFRvIII-targeted therapy and recurred, must have&#xD;
             a tumor sample obtained after their recurrence available for EGFRvIII testing.&#xD;
&#xD;
          -  Age greater than 18 years.&#xD;
&#xD;
          -  If the patient is on dexamethasone, the anticipated dose must be 4 mg/day or less for&#xD;
             at least 5 days prior to apheresis.&#xD;
&#xD;
          -  ECOG performance status of 0 or 1 Documented negative serum HCG for female patients of&#xD;
             child-bearing potential.&#xD;
&#xD;
          -  Participants with adequate organ function as measured by:&#xD;
&#xD;
               -  White blood count greater than or equal to 2500/mm^3; platelets greater than or&#xD;
                  equal to 100,000/mm^3, hemoglobin greater than or equal to 9.0 g/dL; without&#xD;
                  transfusion or growth factor support&#xD;
&#xD;
               -  AST, ALT, GGT, LDH, alkaline phosphatase within 2.5 x upper normal limit, and&#xD;
                  total bilirubin less than or equal to 2.0 mg/dL&#xD;
&#xD;
               -  Serum creatinine less than or equal to 1.5 x upper limit of normal&#xD;
&#xD;
               -  Coagulation tests PT and PTT have to be within normal limits, unless the patient&#xD;
                  has been therapeutically anti-coagulated for previous venous thrombosis.&#xD;
&#xD;
          -  Provide voluntary informed consent for Tissue Screening and Apheresis&#xD;
&#xD;
        Inclusion Criteria Step 2:&#xD;
&#xD;
          1. Subject met all Step 1 Eligibility Criteria.&#xD;
&#xD;
          2. Tumor cells test positive for EGFRvIII expression (by RT-PCR, next generation&#xD;
             sequencing, or immunohistochemistry) and a CART EGFRvIII product has been manufactured&#xD;
             and formulated. Patients who have previously been treated with an EGFRvIII-targeted&#xD;
             therapy and recurred are only eligible if a tumor sample obtained after their&#xD;
             recurrence tests positive for EGFRvIII.&#xD;
&#xD;
          3. Stage of disease:&#xD;
&#xD;
               -  Cohort 1: Patients with first relapse of previously diagnosed primary&#xD;
                  glioblastoma. Recurrence may be determined by imaging and clinical criteria&#xD;
                  alone.&#xD;
&#xD;
               -  Cohort 2: Patients with newly diagnosed glioblastoma with a less than 95%&#xD;
                  resection or greater than or equal to 1 cm^3 of residual disease on the&#xD;
                  post-operative MRI (typically post-operative day 1).&#xD;
&#xD;
          4. If the patient is on dexamethasone, the dose must be 4 mg/day or less prior to&#xD;
             CART-EGFRvIII infusion.&#xD;
&#xD;
          5. It is anticipated that all patients in Cohort 2 will have completed standard of care&#xD;
             external beam radiotherapy and chemotherapy with temozolomide (TMZ) at the time of the&#xD;
             pre-infusion safety visit.&#xD;
&#xD;
          6. Life expectancy less greater than 3 months&#xD;
&#xD;
          7. ECOG performance status of 0 or 1&#xD;
&#xD;
        9. Participants with adequate organ function as measured by:&#xD;
&#xD;
          -  White blood count greater than or equal to 2500/mm^3; platelets greater than or equal&#xD;
             to 100,000/mm^3, hemoglobin greater than or equal to 9.0 g/dL; without transfusion or&#xD;
             growth factor support&#xD;
&#xD;
          -  AST, ALT, GGT, LDH, alkaline phosphatase within 2.5 x upper normal limit, and total&#xD;
             bilirubin less than or equal to 2.0 mg/dL&#xD;
&#xD;
          -  Serum creatinine less than or equal to 1.5 x upper limit of normal&#xD;
&#xD;
          -  Coagulation tests PT and PTT have to be within normal limits, unless the patient has&#xD;
             been therapeutically anti-coagulated for previous venous thrombosis.&#xD;
&#xD;
          -  Adequate cardiac function (greater than EF 55%) 10. Provide voluntary informed consent&#xD;
             for study treatment. 11. Female subjects of reproductive potential must agree to use a&#xD;
             reliable method of contraception.&#xD;
&#xD;
        Exclusion Criteria Step 1:&#xD;
&#xD;
          -  Female subjects of reproductive potential who are pregnant or lactating. Female study&#xD;
             participants of reproductive potential must have a negative serum pregnancy test as&#xD;
             part of Step 1 eligibility confirmation.&#xD;
&#xD;
          -  Uncontrolled active infection.&#xD;
&#xD;
          -  Active or latent chronic hepatitis B [detectable hepatitis B surface antigen (HBsAg)]&#xD;
             or active hepatitis C (positive serology [HCV Ab]) infection.&#xD;
&#xD;
          -  HIV infection.&#xD;
&#xD;
          -  Previous treatment with any gene therapy products.&#xD;
&#xD;
          -  Known addiction to alcohol or illicit drugs.&#xD;
&#xD;
          -  History of allergy or hypersensitivity to study product excipients (human serum&#xD;
             albumin, DMSO, and Dextran 40)&#xD;
&#xD;
        Exclusion Criteria Step 2:&#xD;
&#xD;
          -  Female subjects of reproductive potential who are pregnant or lactating. Female study&#xD;
             participants of reproductive potential must have a negative serum pregnancy test&#xD;
             within two weeks prior to CART-EGFRvIII cell infusion. The safety of this therapy on&#xD;
             unborn children is not known.&#xD;
&#xD;
          -  Uncontrolled active infection.&#xD;
&#xD;
          -  Use of immunosuppressive agents such as cyclosporine, MMF, tacrolimus, or rapamycin&#xD;
             within 4 weeks of enrollment on Step 2.&#xD;
&#xD;
          -  A minimal dose of corticosteroid (dexamethasone up to 4 mg/day) is permitted. Recent&#xD;
             or current use of inhaled steroids is not exclusionary.&#xD;
&#xD;
          -  Previous treatment with any gene therapy products.&#xD;
&#xD;
          -  Subjects or their physicians anticipate use of any of the following concurrent&#xD;
             treatment or medications including: a. Radiosurgery (except for the Standard of Care&#xD;
             Fractionated External Radiation therapy is a part of the protocol regimen in Cohort 2)&#xD;
             b. Chemotherapy (except for the Standard of Care Temozolomide therapy in Cohort 2) c.&#xD;
             Interferon (e.g. Intron-A®) d. Allergy desensitization injections e. Any ongoing&#xD;
             investigational therapeutic medication. f. Bevacizumab&#xD;
&#xD;
          -  Participants who have another cancer diagnosis with history of visceral metastases at&#xD;
             the time of pre-entry evaluation. The following diagnoses are examples that will be&#xD;
             allowed:&#xD;
&#xD;
               -  squamous cell cancer of the skin without known metastasis&#xD;
&#xD;
               -  basal cell cancer of the skin without known metastasis&#xD;
&#xD;
               -  carcinoma in situ of the breast (DCIS or LCIS)&#xD;
&#xD;
               -  carcinoma in situ of the cervix&#xD;
&#xD;
               -  prostate cancer with only PSA recurrence&#xD;
&#xD;
               -  any cancer that has not required systemic therapy (other than hormonal therapies)&#xD;
                  for the past three (3) years.&#xD;
&#xD;
          -  Any uncontrolled active medical disorder that would preclude participation as&#xD;
             outlined.&#xD;
&#xD;
          -  Unstable angina and/or myocardial infarction within 6 months prior to screening&#xD;
&#xD;
          -  Known addiction to alcohol or illicit drugs.&#xD;
&#xD;
          -  History of allergy or hypersensitivity to study product excipients (human serum&#xD;
             albumin, DMSO, and Dextran 40)&#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>Donald O'Rourke, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Abramson Cancer Center at Penn Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Susan Chang, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UCSF</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Abramson Cancer Center of the University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, Brogdon JL, Maus MV. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017 Jul 19;9(399):eaaa0984. doi: 10.1126/scitranslmed.aaa0984.</citation>
    <PMID>28724573</PMID>
  </results_reference>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>August 4, 2014</study_first_submitted>
  <study_first_submitted_qc>August 4, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 5, 2014</study_first_posted>
  <last_update_submitted>June 20, 2023</last_update_submitted>
  <last_update_submitted_qc>June 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 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>
  </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/NCT02209376
org study id: UPCC 35313, 820381
nct id: NCT02209376
lead sponsor: 
collaborator: 
has dmc: Yes
An Open-Label Phase 1 Pilot Study to determine the safety and feasibility of CART-EGFRvIII
      (autologous T cells transduced with a lentiviral vector to express a chimeric antigen
      receptor specific for EGFRvIII) in the treatment of patients with EGFRvIII+ glioblastoma who
      have had their first recurrence as determined by standard imaging or have have residual
      disease after initial resection.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of adverse events
time frame: 2 years
arm group label: Arm 1
arm group type: Experimental
intervention type: Biological
intervention name: CART-EGFRvIII T cells
arm group label: Arm 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Donald O'Rourke, MD
role: Principal Investigator
affiliation: Abramson Cancer Center at Penn Medicine
last name: Susan Chang, MD
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
facility: 
country: United States
citation: O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, Brogdon JL, Maus MV. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017 Jul 19;9(399):eaaa0984. doi: 10.1126/scitranslmed.aaa0984.
PMID: 28724573
responsible party type: Sponsor
mesh term: Glioblastoma