<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/NCT04482933</url>
  </required_header>
  <id_info>
    <org_study_id>PBTC-061</org_study_id>
    <nct_id>NCT04482933</nct_id>
  </id_info>
  <brief_title>HSV G207 With a Single Radiation Dose in Children With Recurrent High-Grade Glioma</brief_title>
  <official_title>Phase II Clinical Trial of HSV G207 With a Single 5 Gy Radiation Dose in Children With Recurrent High-Grade Glioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pediatric Brain Tumor Consortium</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Treovir, LLC</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Pediatric Brain Tumor Consortium</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is a clinical trial to assess the efficacy and confirm the safety of intratumoral&#xD;
      inoculation of G207 (an experimental virus therapy) combined with a single 5 Gy dose of&#xD;
      radiation in recurrent/progressive pediatric high-grade gliomas&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Outcomes for children with recurrent or progressive high-grade glioma (brain tumor) are very&#xD;
      poor, and there are a lack of effective salvage therapies once a patient fails standard&#xD;
      treatments. Novel innovative treatments are greatly needed.&#xD;
&#xD;
      G207 is an oncolytic herpes simplex virus-1 (HSV) that has been successfully engineered to&#xD;
      introduce mutations in the virus that enable it to selectively replicate in and kill cancer&#xD;
      cells, but not normal cells. Replication of G207 in the tumor not only kills the infected&#xD;
      tumor cells, but causes the tumor cell to act as a factory to produce new virus. These virus&#xD;
      particles are released as the tumor cell dies, and can then proceed to infect other tumor&#xD;
      cells in the vicinity, and continue the process of tumor kill. In addition to this direct&#xD;
      oncolytic activity, the virus engenders an anti-tumor immune response; the virus is&#xD;
      immunogenic and produces a debris field which exposes cancer cell antigens to immune cells,&#xD;
      which can target other cancer cells. Thus, the oncolytic effect of the virus and the immune&#xD;
      response that the virus stimulates provide a dual attack against cancer cells. In preclinical&#xD;
      studies, a single 5 Gy dose of radiation within 24 hours of virus inoculation to the tumor&#xD;
      increased virus replication and tumor cell killing. Radiation may also enhance the immune&#xD;
      response against the tumor.&#xD;
&#xD;
      The University of Alabama at Birmingham has conducted three phase I trials of G207 injected&#xD;
      into the recurrent tumor alone or combined with a single dose of radiation in adults with&#xD;
      recurrent high-grade gliomas. In these trials, high doses (up to 3 x 10^9 plaque-forming&#xD;
      units) of virus were safely injected directly into the tumor or surrounding brain tissue&#xD;
      without serious toxicities. Radiographic and neuropathologic evidence of an antitumor&#xD;
      response was seen in some patients. Preclinical laboratory studies have demonstrated that a&#xD;
      variety of aggressive pediatric brain tumor types are sensitive to G207.&#xD;
&#xD;
      A Phase I study of intratumoral G207 alone or combined with a 5 Gy dose of radiation in&#xD;
      children ages 3-18 with biopsy-confirmed recurrent/progressive supratentorial brain tumors&#xD;
      recently completed the highest planned dose level (UAB1472; NCT02457845). The study used a 3&#xD;
      + 3 design with 4 dose cohorts.12 Patients underwent stereotactic placement of up to 4&#xD;
      intratumoral catheters. The following day they received a single controlled-rate infusion of&#xD;
      G207 (1 x 10^7 or 1 x 10^8 pfu) over 6 hours. Cohorts 3 and 4 received a 5 Gy radiation&#xD;
      fraction to the gross tumor volume within 24 hours of G207. Twelve subjects with progressive&#xD;
      high-grade glioma received G207. Twenty adverse events, all grade 1, were attributed to G207.&#xD;
      G207 was determined to be safe and tolerable in children and a recommended Phase 2 was&#xD;
      established (1 x10^8 followed by 5 Gy radiation to the tumor).&#xD;
&#xD;
      This study is a phase II, open-label, single arm clinical trial of G207 alone or combined&#xD;
      with a single low dose of radiation in children with recurrent or progressive high grade&#xD;
      glioma. The primary objective is to assess the efficacy. The secondary objective is to&#xD;
      confirm the safety and tolerability of G207 and to survey for virologic shedding following&#xD;
      G207.&#xD;
&#xD;
      Subjects will receive G207 at 1 x 10^8 plaque-forming units (pfu), intratumorally via&#xD;
      controlled rate infusion through up to 4 silastic catheters over a 6 hour period. The subject&#xD;
      will then receive a single 5 Gy dose of radiation to the tumor within 24 hours of virus&#xD;
      inoculation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">November 15, 2023</start_date>
  <completion_date type="Anticipated">November 15, 2028</completion_date>
  <primary_completion_date type="Anticipated">November 15, 2028</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Phase II Clinical Trial of HSV G207 with a Single 5 Gy Radiation Dose in Children with Recurrent High-Grade Glioma</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy (overall survival)</measure>
    <time_frame>Baseline to 24 months</time_frame>
    <description>To determine efficacy, post progression overall survival (pPD-OS) curve for patients that receive G207 will be compared to historical controls at initial recurrence. Because this is an adjuvant immunovirotherapy that can (a) result in central clearing of a tumor due to cell death and necrosis where virus is infused; (b) elicit a striking immune cell infiltration that creates a pseudoprogression 'phenotype' and (c) produce a delayed anti-tumor response, there is not an adequate response assessment tool to accurately determine an objective response rate or true progression for declaration of progression-free survival. For these reasons, we will compare post-progression overall survival observed on this study to similarly defined outcomes in historical controls.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]</measure>
    <time_frame>Baseline to 15 years</time_frame>
    <description>Safety/tolerability will be assessed by adverse events and laboratory tests. Adverse events will be described and the frequency of events will be tabulated. All events within the first 30 days of G207 administration will be summarized separately and tabulated by event, grade, and by relationship to G207. In addition, any Grade 3 or above toxicity (where toxicity is defined by the CTCAE v5.0) will be summarized separately and tabulated by event and by relationship to G207. Concurrent illnesses will be listed and examined as possible confounders in the treatment response relationship. Concurrent medications will also be listed, as will previous treatments for malignant brain tumors. Effects of concomitant medications and previous treatments for cancer and any potential related side effects will be analyzed and discussed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Virologic Shedding</measure>
    <time_frame>Baseline to 15 years</time_frame>
    <description>Virologic shedding will be assessed from saliva, conjunctiva and blood by polymerase chain reaction (PCR)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Immunologic Response: HSV-1 Antibody Titers</measure>
    <time_frame>Baseline to 12 months</time_frame>
    <description>HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment</description>
  </other_outcome>
  <other_outcome>
    <measure>Immunologic Response: Expression Levels of Peripheral Blood Immune Cells, Cytokines, and Chemokines</measure>
    <time_frame>Baseline to 12 months</time_frame>
    <description>Expression levels will be determined prior to the administration of G207 and at regular intervals after treatment</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlate Radiographic Changes to G207 + 5 Gy Radiation</measure>
    <time_frame>Baseline to 24 months</time_frame>
    <description>MRI of the brain will be checked and radiographic changes assessed in relation to baseline mitotic index, cerebral blood volume and fractional tumor burden</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Performance (Ability to Perform Normal Activities)</measure>
    <time_frame>Baseline to 12 months</time_frame>
    <description>A modified Lansky score (for children under 16 years of age) or Karnofsky score (for children 16 and older) will be recorded and measured serially. The score is a standard performance score that measures overall function of the child with a scale range from 0 (lowest, poorest performance score) to 100 (highest, best performance).</description>
  </other_outcome>
  <other_outcome>
    <measure>Number or Presence of Immune and Neuroinflammatory Cell Populations, Checkpoint Proteins, Stem Cell Markers, and/or HSV Entry Molecules in Tumor Tissue</measure>
    <time_frame>Baseline to 12 months</time_frame>
    <description>The microenvironment of tumor tissue will be surveyed.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Neoplasms</condition>
  <condition>High Grade Glioma</condition>
  <condition>Glioblastoma Multiforme</condition>
  <condition>Malignant Glioma of Brain</condition>
  <condition>Anaplastic Astrocytoma of Brain</condition>
  <condition>High-grade Glioma</condition>
  <condition>Anaplastic Glioma</condition>
  <condition>Giant Cell Glioblastoma</condition>
  <arm_group>
    <arm_group_label>Experimental: HSV G207</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All subjects will receive G207 at 1 x 10^8 plaque-forming units (pfu), intratumorally via controlled rate infusion through up to 4 silastic catheters over a 6 hour period. The subject will then receive a single 5 Gy dose of radiation to the tumor within 24 hours of virus inoculation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Biological G207</intervention_name>
    <description>Single dose of HSV-1 (G207) infused through catheters into region(s) of tumor defined by MRI</description>
    <arm_group_label>Experimental: HSV G207</arm_group_label>
    <other_name>Experimental: HSV G207</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients meeting the following inclusion criteria will be eligible for the study:&#xD;
&#xD;
          -  Patient must be ≥ 3 at initial diagnosis but &lt; 22 years of age at the time of&#xD;
             enrollment on this study.&#xD;
&#xD;
          -  Patients must have a histologically confirmed diagnosis of high-grade glioma&#xD;
             regardless of molecular characterization that is recurrent or progressive. All tumors&#xD;
             must have histologic verification at either the time of diagnosis or recurrence.&#xD;
&#xD;
          -  Patients are only eligible after their first progression following prior surgery and&#xD;
             radiotherapy&#xD;
&#xD;
          -  Lesion must be ≥ 1.0 cm in longest dimension and surgically accessible as determined&#xD;
             by contrast-enhanced MRI&#xD;
&#xD;
          -  For patients with tumors &gt; 4.0 cm without an adjacent cavity, the neurosurgeon must be&#xD;
             confident that the tumor can be debulked to ≤ 4.0 cm for eligibility.&#xD;
&#xD;
          -  Multifocal disease on the ipsilateral side is eligible if at least one catheter can be&#xD;
             placed in all multifocal areas&#xD;
&#xD;
          -  Tumor size will be determined using the maximal 2-dimensional cross-sectional tumor&#xD;
             measurements, transverse x width, using either T1 images or T2/FLAIR images for&#xD;
             non-enhancing tumors.&#xD;
&#xD;
          -  Performance score ≥ 60% (Karnofsky for children ≥16 years old; modified Lansky for&#xD;
             children &lt; 16 years old)&#xD;
&#xD;
          -  Patients with neurological deficits should have deficits that are stable for ≥ 1 week&#xD;
             prior to enrollment. A baseline detailed neurological exam should clearly document the&#xD;
             neurological status of the patient at the time of enrollment on the study&#xD;
&#xD;
          -  Prior therapy: Patients must have received prior surgery and radiotherapy and&#xD;
             recovered from the acute treatment related toxicities (defined as ≤ Grade 1 if not&#xD;
             defined in eligibility criteria; excludes alopecia) prior to enrollment.&#xD;
&#xD;
          -  Radiation: Patients must have received their last fraction of radiation (≥ 54 Gy) ≥ 3&#xD;
             months prior to study entry. Patients must have received local palliative radiation ≥&#xD;
             28 days prior to study entry&#xD;
&#xD;
          -  Myelosuppressive chemotherapy: Patients must have received their last dose of known&#xD;
             myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least&#xD;
             42 days if nitrosourea.&#xD;
&#xD;
          -  Investigational/Biologic agents: patients must have recovered from any acute&#xD;
             toxicities potentially related to the agent and received the last dose ≥ 7 days prior&#xD;
             to entering this study (this period must be extended beyond the time during which&#xD;
             adverse events are known to occur for agents with known adverse events ≥ 7 days). For&#xD;
             viral therapy or cellular therapy, patients must have received therapy ≥ 3 months&#xD;
             prior to study entry and have recovered from all acute toxicities potentially related&#xD;
             to the agent.&#xD;
&#xD;
          -  Monoclonal antibodies: Patient must have received their last dose of the&#xD;
             investigational or biologic agent ≥ 7 days prior to study enrollment.&#xD;
&#xD;
             o For agents that have known adverse events occurring beyond 7 days after&#xD;
             administration, this period must be extended beyond the time during which adverse&#xD;
             events are known to occur.&#xD;
&#xD;
          -  Immune Effector Cell (IEC) Therapy (e.g., CAR T cells) For viral therapy or cellular&#xD;
             therapy, patients must have received therapy ≥ 3 months prior to study enrollment.&#xD;
&#xD;
          -  Stem Cell Transplant: Patient must be:&#xD;
&#xD;
          -  ≥ 6 months since allogeneic stem cell transplant prior to enrollment with no evidence&#xD;
             of active graft vs. host disease.&#xD;
&#xD;
          -  ≥ 3 months since autologous stem cell transplant prior to enrollment.&#xD;
&#xD;
        Neurologic Status:&#xD;
&#xD;
          -  Patients with neurological deficits should have deficits that are stable for a minimum&#xD;
             of 1 week prior to enrollment.&#xD;
&#xD;
             o A baseline detailed neurological exam should clearly document the neurological&#xD;
             status of the patient at the time of enrollment on the study.&#xD;
&#xD;
          -  Patients with seizure disorders may be enrolled if seizures are well controlled.&#xD;
&#xD;
          -  Patients must have adequate organ and marrow function as defined below:&#xD;
&#xD;
          -  Absolute neutrophil count &gt; 1.0 x 109 cells/L&#xD;
&#xD;
          -  Platelets &gt; 100 x 109 cells/L (unsupported, defined as no platelet transfusion within&#xD;
             7 days)&#xD;
&#xD;
          -  Hemoglobin ≥ 8 g/dL (may receive transfusions)&#xD;
&#xD;
          -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  PT/INR, PTT ≤ 1.5 x ULN&#xD;
&#xD;
          -  ALT(SGPT) and AST (SGOT) &lt; 3 x institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Albumin ≥ 3 g/dL&#xD;
&#xD;
          -  Serum creatinine based on age/gender as noted in Table 2. Patients that do not meet&#xD;
             the criteria in Table 2 but have a Cystatin C, 24-hour Creatinine Clearance or GFR&#xD;
             (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2 are eligible.&#xD;
&#xD;
        Age Maximum Serum Creatinine (mg/dL) Male Female 1 to &lt; 2 years 0.6 0.6 2 to &lt; 6 years 0.8&#xD;
        0.8 6 to &lt; 10 years 1 1 10 to &lt; 13 years 1.2 1.2 13 to &lt; 16 years 1.5 1.4&#xD;
&#xD;
        ≥ 16 years 1.7 1.4&#xD;
&#xD;
        Corticosteroids Patients who are receiving dexamethasone must be on a stable or decreasing&#xD;
        dose for at least 1 week prior to enrollment.&#xD;
&#xD;
        Growth Factors Patients must be off all colony-forming growth factor(s) for at least 1 week&#xD;
        prior to enrollment (e.g., filgrastim, sargramostim, or erythropoietin). Two (2) weeks must&#xD;
        have elapsed if the patient received a long-acting formulation.&#xD;
&#xD;
        Pregnancy Prevention Patients of childbearing or child fathering potential must be willing&#xD;
        to use a medically acceptable form of birth control, which includes abstinence, while being&#xD;
        treated on this study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Pregnant women are excluded from this study. Lactating females are not eligible unless they&#xD;
        have agreed not to breastfeed their infants&#xD;
&#xD;
        Concurrent Illness&#xD;
&#xD;
          -  Patients with any clinically significant unrelated systemic illness (serious&#xD;
             infections or significant cardiac, pulmonary, hepatic or other organ dysfunction),&#xD;
             that in the opinion of the investigator would compromise the patient's ability to&#xD;
             undergo surgery and/or tolerate protocol therapy, put them at additional risk for&#xD;
             toxicity or would interfere with the study procedures or results.&#xD;
&#xD;
          -  Known HIV seropositivity.&#xD;
&#xD;
          -  Patients with a prior or concurrent malignancy whose natural history or treatment has&#xD;
             the potential to interfere with the safety or efficacy assessment of the&#xD;
             investigational regimen for this trial.&#xD;
&#xD;
          -  Patients with a secondary high-grade glioma are ineligible.&#xD;
&#xD;
          -  Patient with primary tumor involving the cerebellum, brainstem or spinal cord or that&#xD;
             would require surgical access through a ventricle in order to deliver the prescribed&#xD;
             protocol treatment.&#xD;
&#xD;
          -  Metastatic disease or diffuse, widespread, abnormal tumor pattern involving 3 or more&#xD;
             lobes of the brain&#xD;
&#xD;
          -  Tumor with evidence of clinically significant uncal herniation or midline shift, or&#xD;
             evidence of ventricular obstruction from tumor or tonsillar herniation&#xD;
&#xD;
          -  Diagnosis of encephalitis or CNS infection &lt; 3 months prior, or receiving ongoing&#xD;
             treatment for encephalitis, CNS infection or multiple sclerosis&#xD;
&#xD;
        Concomitant Medications&#xD;
&#xD;
          -  Patients who are receiving any other anti-cancer or investigational drug therapy are&#xD;
             ineligible.&#xD;
&#xD;
          -  Patients who are receiving ≥ 1.5 mg of dexamethasone (or ≥ 10 mg of prednisone) daily&#xD;
&#xD;
          -  Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir,&#xD;
             penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir)&#xD;
&#xD;
          -  Patients may not be on immunosuppressive therapy, including corticosteroids (except&#xD;
             for patients receiving &lt; 1.5 mg of dexamethasone or &lt; 10 mg of prednisone daily) at&#xD;
             time of enrollment. However, patients who require intermittent use of bronchodilators&#xD;
             or topical steroids will not be excluded from the study.&#xD;
&#xD;
        Inability to participate Patients who in the opinion of the investigator are unwilling or&#xD;
        unable to return for required follow-up visits or obtain follow-up studies required to&#xD;
        assess toxicity to therapy or to adhere to drug administration plan, other study&#xD;
        procedures, and study restrictions.&#xD;
&#xD;
        Other Infectious Diseases Patients who are known to be HIV seropositive are ineligible.&#xD;
        Patient must have documented evidence of negative tests for the presence of Human&#xD;
        Immunodeficiency Virus (HIV).&#xD;
&#xD;
        Prior Cranial Spinal Irradiation Patients who received cranial spinal irradiation (CSI) are&#xD;
        ineligible.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gregory Friedman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Alabama at Birmingham</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Anneliese Rosdil, MSN</last_name>
    <phone>901-293-1239</phone>
    <email>arosdil@stjude.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Children's of Alabama</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
    <contact>
      <last_name>Kara Kachurak, CRNP</last_name>
      <phone>205-638-9285</phone>
      <email>kkachurak@peds.uab.edu</email>
    </contact>
    <contact_backup>
      <last_name>Gregory Friedman, M.D.</last_name>
      <phone>205-638-9285</phone>
      <email>gfriedman@peds.uab.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Gregory Friedman, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>July 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 23, 2020</study_first_posted>
  <last_update_submitted>June 28, 2023</last_update_submitted>
  <last_update_submitted_qc>June 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 29, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Brain Tumor, Recurrent</keyword>
  <keyword>glioma</keyword>
  <keyword>oncolytic virotherapy</keyword>
  <keyword>immunotherapy</keyword>
  <keyword>immunovirotherapy</keyword>
  <keyword>neoplasm</keyword>
  <keyword>progressive</keyword>
  <keyword>virus</keyword>
  <keyword>HSV</keyword>
  <keyword>herpes virus</keyword>
  <keyword>herpes simplex virus</keyword>
  <keyword>oncolytic virus</keyword>
  <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>Astrocytoma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04482933
org study id: PBTC-061
nct id: NCT04482933
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study is a clinical trial to assess the efficacy and confirm the safety of intratumoral
      inoculation of G207 (an experimental virus therapy) combined with a single 5 Gy dose of
      radiation in recurrent/progressive pediatric high-grade gliomas
Outcomes for children with recurrent or progressive high-grade glioma (brain tumor) are very
      poor, and there are a lack of effective salvage therapies once a patient fails standard
      treatments. Novel innovative treatments are greatly needed.

      G207 is an oncolytic herpes simplex virus-1 (HSV) that has been successfully engineered to
      introduce mutations in the virus that enable it to selectively replicate in and kill cancer
      cells, but not normal cells. Replication of G207 in the tumor not only kills the infected
      tumor cells, but causes the tumor cell to act as a factory to produce new virus. These virus
      particles are released as the tumor cell dies, and can then proceed to infect other tumor
      cells in the vicinity, and continue the process of tumor kill. In addition to this direct
      oncolytic activity, the virus engenders an anti-tumor immune response; the virus is
      immunogenic and produces a debris field which exposes cancer cell antigens to immune cells,
      which can target other cancer cells. Thus, the oncolytic effect of the virus and the immune
      response that the virus stimulates provide a dual attack against cancer cells. In preclinical
      studies, a single 5 Gy dose of radiation within 24 hours of virus inoculation to the tumor
      increased virus replication and tumor cell killing. Radiation may also enhance the immune
      response against the tumor.

      The University of Alabama at Birmingham has conducted three phase I trials of G207 injected
      into the recurrent tumor alone or combined with a single dose of radiation in adults with
      recurrent high-grade gliomas. In these trials, high doses (up to 3 x 10^9 plaque-forming
      units) of virus were safely injected directly into the tumor or surrounding brain tissue
      without serious toxicities. Radiographic and neuropathologic evidence of an antitumor
      response was seen in some patients. Preclinical laboratory studies have demonstrated that a
      variety of aggressive pediatric brain tumor types are sensitive to G207.

      A Phase I study of intratumoral G207 alone or combined with a 5 Gy dose of radiation in
      children ages 3-18 with biopsy-confirmed recurrent/progressive supratentorial brain tumors
      recently completed the highest planned dose level (UAB1472; NCT02457845). The study used a 3
      + 3 design with 4 dose cohorts.12 Patients underwent stereotactic placement of up to 4
      intratumoral catheters. The following day they received a single controlled-rate infusion of
      G207 (1 x 10^7 or 1 x 10^8 pfu) over 6 hours. Cohorts 3 and 4 received a 5 Gy radiation
      fraction to the gross tumor volume within 24 hours of G207. Twelve subjects with progressive
      high-grade glioma received G207. Twenty adverse events, all grade 1, were attributed to G207.
      G207 was determined to be safe and tolerable in children and a recommended Phase 2 was
      established (1 x10^8 followed by 5 Gy radiation to the tumor).

      This study is a phase II, open-label, single arm clinical trial of G207 alone or combined
      with a single low dose of radiation in children with recurrent or progressive high grade
      glioma. The primary objective is to assess the efficacy. The secondary objective is to
      confirm the safety and tolerability of G207 and to survey for virologic shedding following
      G207.

      Subjects will receive G207 at 1 x 10^8 plaque-forming units (pfu), intratumorally via
      controlled rate infusion through up to 4 silastic catheters over a 6 hour period. The subject
      will then receive a single 5 Gy dose of radiation to the tumor within 24 hours of virus
      inoculation.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Phase II Clinical Trial of HSV G207 with a Single 5 Gy Radiation Dose in Children with Recurrent High-Grade Glioma
primary purpose: Treatment
masking: None (Open Label)
measure: Efficacy (overall survival)
time frame: Baseline to 24 months
description: To determine efficacy, post progression overall survival (pPD-OS) curve for patients that receive G207 will be compared to historical controls at initial recurrence. Because this is an adjuvant immunovirotherapy that can (a) result in central clearing of a tumor due to cell death and necrosis where virus is infused; (b) elicit a striking immune cell infiltration that creates a pseudoprogression 'phenotype' and (c) produce a delayed anti-tumor response, there is not an adequate response assessment tool to accurately determine an objective response rate or true progression for declaration of progression-free survival. For these reasons, we will compare post-progression overall survival observed on this study to similarly defined outcomes in historical controls.
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
time frame: Baseline to 15 years
description: Safety/tolerability will be assessed by adverse events and laboratory tests. Adverse events will be described and the frequency of events will be tabulated. All events within the first 30 days of G207 administration will be summarized separately and tabulated by event, grade, and by relationship to G207. In addition, any Grade 3 or above toxicity (where toxicity is defined by the CTCAE v5.0) will be summarized separately and tabulated by event and by relationship to G207. Concurrent illnesses will be listed and examined as possible confounders in the treatment response relationship. Concurrent medications will also be listed, as will previous treatments for malignant brain tumors. Effects of concomitant medications and previous treatments for cancer and any potential related side effects will be analyzed and discussed.
measure: Virologic Shedding
time frame: Baseline to 15 years
description: Virologic shedding will be assessed from saliva, conjunctiva and blood by polymerase chain reaction (PCR)
measure: Immunologic Response: HSV-1 Antibody Titers
time frame: Baseline to 12 months
description: HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment
measure: Immunologic Response: Expression Levels of Peripheral Blood Immune Cells, Cytokines, and Chemokines
time frame: Baseline to 12 months
description: Expression levels will be determined prior to the administration of G207 and at regular intervals after treatment
measure: Correlate Radiographic Changes to G207 + 5 Gy Radiation
time frame: Baseline to 24 months
description: MRI of the brain will be checked and radiographic changes assessed in relation to baseline mitotic index, cerebral blood volume and fractional tumor burden
measure: Change in Performance (Ability to Perform Normal Activities)
time frame: Baseline to 12 months
description: A modified Lansky score (for children under 16 years of age) or Karnofsky score (for children 16 and older) will be recorded and measured serially. The score is a standard performance score that measures overall function of the child with a scale range from 0 (lowest, poorest performance score) to 100 (highest, best performance).
measure: Number or Presence of Immune and Neuroinflammatory Cell Populations, Checkpoint Proteins, Stem Cell Markers, and/or HSV Entry Molecules in Tumor Tissue
time frame: Baseline to 12 months
description: The microenvironment of tumor tissue will be surveyed.
arm group label: Experimental: HSV G207
arm group type: Experimental
description: All subjects will receive G207 at 1 x 10^8 plaque-forming units (pfu), intratumorally via controlled rate infusion through up to 4 silastic catheters over a 6 hour period. The subject will then receive a single 5 Gy dose of radiation to the tumor within 24 hours of virus inoculation.
intervention type: Drug
intervention name: Biological G207
description: Single dose of HSV-1 (G207) infused through catheters into region(s) of tumor defined by MRI
arm group label: Experimental: HSV G207
other name: Experimental: HSV G207
criteria: 
gender: All
minimum age: 3 Years
maximum age: 21 Years
healthy volunteers: No
last name: Gregory Friedman, MD
role: Principal Investigator
affiliation: University of Alabama at Birmingham
last name: Anneliese Rosdil, MSN
phone: 901-293-1239
email: arosdil@stjude.org
facility: 
contact: 
contact backup: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Glioma
mesh term: Astrocytoma
sharing ipd: No