<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/NCT01678352</url>
  </required_header>
  <id_info>
    <org_study_id>11-136</org_study_id>
    <nct_id>NCT01678352</nct_id>
  </id_info>
  <brief_title>Imiquimod and Tumor Lysate Vaccine Immunotherapy in Adults With High Risk or Recurrent Grade II Gliomas</brief_title>
  <official_title>A Pilot Study to Evaluate the Effects of Imiquimod and Tumor Lysate Vaccine Immunotherapy for Adults With High Risk or Recurrent/Post-Chemotherapy WHO Grade II Gliomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Frank Lieberman</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a pilot study of a vaccination regime that is designed to efficiently induce&#xD;
      anti-tumor T-cell responses in patients with WHO grade II glioma. The proposed regime with&#xD;
      BTIC Lysate in combination with imiquimod, an FDA-approved immune response modifier will&#xD;
      induce potent anti-glioma immune response with minimal or no toxicity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      To determine the response rate and magnitude of CD8+ T-cell responses against the&#xD;
      Imiquimod/BTIC lysate-based vaccines in post-vaccine PBMC using IFN- ELISPOT. ELISPOT assays&#xD;
      indicate functional status of the antigen-specific T cells as cytokine-expression, and we are&#xD;
      particularly interested in Type-1 (i.e. IFN expressing) T cell response. Therefore, IFN&#xD;
      ELISPOT will be used as the primary assay for the immunological endpoint.&#xD;
&#xD;
      Using flow-cytometry, we will also evaluate the numbers of lymphocyte subsets such as CD4+ T&#xD;
      cells, CD4+/Foxp3+ regulatory T cells in an exploratory manner. In addition, in participants&#xD;
      who undergo surgical debulking of the progressing tumor, if the tumor tissue is available,&#xD;
      infiltration of antigen-specific CTLs will be evaluated by flow cytometry of&#xD;
      tumor-infiltrating lymphocytes with the Imiquimod/BTIC lysate-based vaccine-targeted GAA&#xD;
      specific MHC-tetramers. In addition, serological responses will be evaluated with&#xD;
      flow-cytometry of BTIC cells as well as western blotting. These plans (in this paragraph) are&#xD;
      immunological evaluations; however, do not compose the primary endpoints due to their&#xD;
      exploratory nature.&#xD;
&#xD;
      We will determine whether it is safe to administer Imiquimod/BTIC lysate-based vaccines in&#xD;
      patients with grade II gliomas. Endpoints will therefore include incidence and severity of&#xD;
      adverse events, using standard criteria as well as close clinical follow-up as would be&#xD;
      performed normally in this group of participants following vaccinations. All reported or&#xD;
      observed toxicities and adverse events at all clinic visits will be graded, documented and&#xD;
      reported according to a standard toxicity table, the Common Terminology Criteria for Adverse&#xD;
      Events (CTCAE) version 4.0&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">November 8, 2018</completion_date>
  <primary_completion_date type="Actual">November 8, 2017</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose limiting toxicity (DLT)</measure>
    <time_frame>Two Years</time_frame>
    <description>The incidence and severity of adverse events associated with the vaccine regime will be assessed according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE), as follows:&#xD;
. Grade 3-5 vaccine related allergic reaction&#xD;
. Grade 3-5 organ toxicity (cardiac, dermatologic (excluding localized skin reaction), gastrointestinal, hepatic, pulmonary, renal/genitourinary, or neurologic) not pre-existing or due to the underlying malignancy and occurring within 28 days of vaccination and of any length in duration&#xD;
. Grade 2 -5 autoimmune reactions (such as hypothyroidism)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Induction of BTIC Lysate-specific T-cell response</measure>
    <time_frame>Two Years</time_frame>
    <description>We will determine the response rate and magnitude of immune response in post-vaccine peripheral blood mononuclear cells (PBMC) against the BTIC Lysate in response to this form of vaccine, using IFN-enzyme-linked immuno-spot (ELISPOT) assays.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>High Risk WHO Grade II Glioma</condition>
  <condition>Recurrent/Post-Chemotherapy WHO Grade II Glioma</condition>
  <arm_group>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients must have undergone surgery or biopsy alone (no postoperative radiation or chemotherapy) and have a baseline MRI scan (within 4 weeks of the first vaccine) that shows stable disease or regression (no progression from the initial surgery/biopsy).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients received surgery or biopsy and radiation therapy (RT) (including fractionated external beam radiation therapy and/or stereotactic radiosurgery), which was completed ≥ 6 months prior to enrollment, and have a baseline MRI scan within 4 weeks prior to the first vaccine that shows stable disease or regression.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with recurrent WHO grade 2 glioma may have received prior external beam radiotherapy and/or chemotherapy. Patients with stable WHO grade 2 glioma must have had prior chemotherapy (at least one cycle of Temozolomide or PCV-based chemotherapy). With regard to the prior therapy in Cohort 3, patients may have had treatment for no more than 2 prior relapses. Relapse is defined as progression following initial therapy (i.e. radiation +/- chemo if that was used as initial therapy) or observation of stable disease. The intent therefore is that patients may have had 3 prior therapies (initial therapy and treatment for 2 relapses). If the patient had a surgical resection for relapsed disease, and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered as 1 relapse.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Tumor Lysate Vaccine</intervention_name>
    <description>Cohort 1 Cohort 2 Cohort 3</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Imiquimod</intervention_name>
    <description>Cohort 1 Cohort 2 Cohort 3</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <other_name>Aldara</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Cohort 1 and 2: Age ≥18 year old with histologically diagnosed World Health&#xD;
             Organization (WHO) grade II astrocytoma or oligoastrocytoma with &quot;high-risk&quot; factors -&#xD;
             defined as:&#xD;
&#xD;
               -  age ≥ 40 with any extent resection;&#xD;
&#xD;
               -  age 18-39 with incomplete resection (post-op MRI showing &gt;1cm residual disease,&#xD;
                  based on the maximum dimension of residual T2 or fluid-attenuated&#xD;
                  inversion-recovery [FLAIR] abnormality from the edge of the surgical cavity&#xD;
                  either laterally, anteroposteriorly, or superoinferiorly) or&#xD;
&#xD;
               -  age 18-39 with neurosurgeon-defined gross total resection (GTR) but the tumor&#xD;
                  size is ≥ 4 cm (the maximum preoperative tumor diameter, based on the axial&#xD;
                  and/or coronal T2 or FLAIR MR images) Cohort 3: Age ≥18 year old with&#xD;
                  histologically diagnosed WHO grade II glioma with recurrence&#xD;
&#xD;
               -  Karnofsky performance status ≥ 60%&#xD;
&#xD;
               -  Clinically stable and off corticosteroids for at least 4 weeks prior to study&#xD;
                  enrollment&#xD;
&#xD;
               -  Adequate organ function within 14 days of study registration including:&#xD;
&#xD;
               -  Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count&#xD;
                  (ANC) ≥1.0 x 109/L, platelets ≥100 x 109/L; hemoglobin ≥ 8 g/dL&#xD;
&#xD;
               -  Hepatic: - Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age and SGPT&#xD;
                  (ALT) ≤ 2.5 x upper limit of normal (ULN) for age&#xD;
&#xD;
               -  Renal: Normal serum creatinine or creatinine clearance ≥60 ml/min/1.73 m2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of immune system abnormalities such as hyperimmunity (e.g., autoimmune&#xD;
             diseases) that required systemic immunosuppression therapy and hypoimmunity (e.g.,&#xD;
             myelodysplastic disorders, marrow failures, AIDS, ongoing pregnancy, transplant&#xD;
             immunosuppression)&#xD;
&#xD;
          -  Any isolated laboratory abnormality suggestive of a serious autoimmune disease (e.g.&#xD;
             hypothyroidism)&#xD;
&#xD;
          -  Any conditions that could potentially alter immune function (AIDS, multiple sclerosis,&#xD;
             diabetes, renal failure)&#xD;
&#xD;
          -  Receiving ongoing treatment with immunosuppressive drugs, excluding those patients&#xD;
             requiring dexamethasone for treatment of tumor-related edema&#xD;
&#xD;
          -  Currently receiving any investigational agents or registration on another therapy&#xD;
             based trial&#xD;
&#xD;
          -  Pregnant or lactating&#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>Frank Lieberman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Pittsburgh Medical Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>August 30, 2012</study_first_submitted>
  <study_first_submitted_qc>September 4, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2012</study_first_posted>
  <last_update_submitted>February 20, 2020</last_update_submitted>
  <last_update_submitted_qc>February 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Frank Lieberman</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>Glioma</keyword>
  <keyword>Vaccine</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>WHO Grade II</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Imiquimod</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01678352
org study id: 11-136
nct id: NCT01678352
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated device: No
This is a pilot study of a vaccination regime that is designed to efficiently induce
      anti-tumor T-cell responses in patients with WHO grade II glioma. The proposed regime with
      BTIC Lysate in combination with imiquimod, an FDA-approved immune response modifier will
      induce potent anti-glioma immune response with minimal or no toxicity.
To determine the response rate and magnitude of CD8+ T-cell responses against the
      Imiquimod/BTIC lysate-based vaccines in post-vaccine PBMC using IFN- ELISPOT. ELISPOT assays
      indicate functional status of the antigen-specific T cells as cytokine-expression, and we are
      particularly interested in Type-1 (i.e. IFN expressing) T cell response. Therefore, IFN
      ELISPOT will be used as the primary assay for the immunological endpoint.

      Using flow-cytometry, we will also evaluate the numbers of lymphocyte subsets such as CD4+ T
      cells, CD4+/Foxp3+ regulatory T cells in an exploratory manner. In addition, in participants
      who undergo surgical debulking of the progressing tumor, if the tumor tissue is available,
      infiltration of antigen-specific CTLs will be evaluated by flow cytometry of
      tumor-infiltrating lymphocytes with the Imiquimod/BTIC lysate-based vaccine-targeted GAA
      specific MHC-tetramers. In addition, serological responses will be evaluated with
      flow-cytometry of BTIC cells as well as western blotting. These plans (in this paragraph) are
      immunological evaluations; however, do not compose the primary endpoints due to their
      exploratory nature.

      We will determine whether it is safe to administer Imiquimod/BTIC lysate-based vaccines in
      patients with grade II gliomas. Endpoints will therefore include incidence and severity of
      adverse events, using standard criteria as well as close clinical follow-up as would be
      performed normally in this group of participants following vaccinations. All reported or
      observed toxicities and adverse events at all clinic visits will be graded, documented and
      reported according to a standard toxicity table, the Common Terminology Criteria for Adverse
      Events (CTCAE) version 4.0
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose limiting toxicity (DLT)
time frame: Two Years
description: The incidence and severity of adverse events associated with the vaccine regime will be assessed according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE), as follows:
. Grade 3-5 vaccine related allergic reaction
. Grade 3-5 organ toxicity (cardiac, dermatologic (excluding localized skin reaction), gastrointestinal, hepatic, pulmonary, renal/genitourinary, or neurologic) not pre-existing or due to the underlying malignancy and occurring within 28 days of vaccination and of any length in duration
. Grade 2 -5 autoimmune reactions (such as hypothyroidism)
measure: Induction of BTIC Lysate-specific T-cell response
time frame: Two Years
description: We will determine the response rate and magnitude of immune response in post-vaccine peripheral blood mononuclear cells (PBMC) against the BTIC Lysate in response to this form of vaccine, using IFN-enzyme-linked immuno-spot (ELISPOT) assays.
arm group label: Cohort 1
arm group type: Experimental
description: Patients must have undergone surgery or biopsy alone (no postoperative radiation or chemotherapy) and have a baseline MRI scan (within 4 weeks of the first vaccine) that shows stable disease or regression (no progression from the initial surgery/biopsy).
arm group label: Cohort 2
arm group type: Experimental
description: Patients received surgery or biopsy and radiation therapy (RT) (including fractionated external beam radiation therapy and/or stereotactic radiosurgery), which was completed ≥ 6 months prior to enrollment, and have a baseline MRI scan within 4 weeks prior to the first vaccine that shows stable disease or regression.
arm group label: Cohort 3
arm group type: Experimental
description: Patients with recurrent WHO grade 2 glioma may have received prior external beam radiotherapy and/or chemotherapy. Patients with stable WHO grade 2 glioma must have had prior chemotherapy (at least one cycle of Temozolomide or PCV-based chemotherapy). With regard to the prior therapy in Cohort 3, patients may have had treatment for no more than 2 prior relapses. Relapse is defined as progression following initial therapy (i.e. radiation +/- chemo if that was used as initial therapy) or observation of stable disease. The intent therefore is that patients may have had 3 prior therapies (initial therapy and treatment for 2 relapses). If the patient had a surgical resection for relapsed disease, and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered as 1 relapse.
intervention type: Biological
intervention name: Tumor Lysate Vaccine
description: Cohort 1 Cohort 2 Cohort 3
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
intervention type: Drug
intervention name: Imiquimod
description: Cohort 1 Cohort 2 Cohort 3
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
other name: Aldara
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Frank Lieberman, MD
role: Principal Investigator
affiliation: University of Pittsburgh
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Frank Lieberman
investigator title: MD
mesh term: Glioma
mesh term: Recurrence
mesh term: Imiquimod