<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/NCT03043391</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00071228</org_study_id>
    <nct_id>NCT03043391</nct_id>
  </id_info>
  <brief_title>Phase 1b Study PVSRIPO for Recurrent Malignant Glioma in Children</brief_title>
  <official_title>Phase Ib Study of Oncolytic Polio/Rhinovirus Recombinant Against Recurrent Malignant Glioma in Children</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Istari Oncology, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Solving Kids' Cancer</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Andrew McDonough B+ Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Istari Oncology, Inc.</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>
      The purpose of the study is to confirm the safety of the selected dose and potential toxicity&#xD;
      of oncolytic poliovirus (PV) immunotherapy with PVSRIPO for pediatric patients with recurrent&#xD;
      WHO grade III or IV malignant glioma, but evidence for efficacy will also be sought. The&#xD;
      primary objective is to confirm the safety of the selected dose of PVSRIPO when delivered&#xD;
      intracerebrally by convection-enhanced delivery (CED) in children with recurrent WHO Grade&#xD;
      III malignant glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic&#xD;
      oligodendroglioma, anaplastic pleomorphic xanthoastrocytoma) or WHO Grade IV malignant glioma&#xD;
      (glioblastoma, gliosarcoma). A secondary objective is to estimate overall survival (OS) in&#xD;
      this population.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PVSRIPO will be delivered intratumorally by CED using an intracerebral catheter placed within&#xD;
      the enhancing portion of the tumor. The population group are patients with recurrent WHO&#xD;
      grade III or IV malignant glioma who are aged 12 through 21 years old. After a single dose of&#xD;
      PVSRIPO, subjects will return for periodic visits to monitor tumor status, adverse events,&#xD;
      and changes in blood immune profiles. A maximum of 12 pediatric patients will be treated with&#xD;
      PVSRIPO, and then carefully monitored for safety for at least a year after treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">December 5, 2017</start_date>
  <completion_date type="Anticipated">March 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2021</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>
    <intervention_model_description>Phase Ib study to evaluate feasibility, safety, and preliminary evidence of efficacy of the optimal adult dose in a pediatric population</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of participants with unacceptable toxicity</measure>
    <time_frame>14 days after treatment with PVSRIPO</time_frame>
    <description>Percentage of participants with unacceptable toxicity during the 14-day period post-PVSRIPO treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>24-month overall survival</measure>
    <time_frame>24 months after administration of PVSRIPO</time_frame>
    <description>The percentage of participants alive at 24 months after the administration of PVSRIPO. Overall survival is defined as the time from the date of administration of PVSRIPO until the date of death, or the date of last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Malignant Glioma</condition>
  <condition>Anaplastic Astrocytoma</condition>
  <condition>Anaplastic Oligoastrocytoma</condition>
  <condition>Anaplastic Oligodendroglioma</condition>
  <condition>Glioblastoma</condition>
  <condition>Gliosarcoma</condition>
  <condition>Atypical Teratoid/Rhabdoid Tumor of Brain</condition>
  <condition>Medulloblastoma</condition>
  <condition>Ependymoma</condition>
  <condition>Pleomorphic Xanthoastrocytoma of Brain</condition>
  <condition>Embryonal Tumor of Brain</condition>
  <arm_group>
    <arm_group_label>Polio/Rhinovirus Recombinant (PVSRIPO)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PVSRIPO is an altered form of the live polio vaccine. It was produced by removing a piece of the virus and replacing it with a piece from a common cold virus. This was done to make sure PVSRIPO cannot cause polio even when injected into the brain.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Polio/Rhinovirus Recombinant (PVSRIPO)</intervention_name>
    <description>PVSRIPO will be delivered intratumorally by convection-enhanced delivery (CED) using an intracerebral catheter placed within the enhancing portion of the tumor. A stereotactic biopsy will be performed prior to virus administration. Immediately following the stereotactically-guided tumor biopsy, a catheter will be implanted in the operating room at a site the same or different from that used for the biopsy using sterile techniques under general anesthesia. The entire volume of PVSRIPO to be delivered will be pre-loaded into a syringe by the investigational pharmacist and connected to the catheter under sterile conditions in the Pediatric Intensive Care Unit (PICU) just prior to beginning of infusion.</description>
    <arm_group_label>Polio/Rhinovirus Recombinant (PVSRIPO)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have a recurrent supratentorial WHO Grade III malignant glioma&#xD;
             (anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma,&#xD;
             anaplastic pleomorphic xanthoastrocytoma, ependymoma) or WHO Grade IV malignant&#xD;
             glioma, medulloblastoma, or atypical teratoid/rhabdoid tumor (ATRT) based on imaging&#xD;
             studies with measurable disease (≥ 1 cm and ≤ 5.5 cm). The prior histopathology must&#xD;
             be consistent with a World Health Organization (WHO) Grade III or IV malignant tumor&#xD;
             confirmed by the study pathologist, Roger McLendon, or his designee.&#xD;
&#xD;
          -  There is no standard of care treatment for children with Grade III/IV gliomas;&#xD;
             however, patients must have received some form of definitive treatment, i.e., standard&#xD;
             therapy with known clinical benefit, for their initial diagnosis prior to their&#xD;
             recurrence/progression. Definitive treatment includes maximal safe resection (if&#xD;
             possible) and radiation therapy with or without chemotherapy. (Please note that&#xD;
             patients who are unable to receive radiation therapy due to genetic disorders that put&#xD;
             them at significant risk for radiation-induced secondary malignancies (i.e., Gorlin's&#xD;
             syndrome or NF1 mutation) are still eligible to participate).&#xD;
&#xD;
          -  Due to the potential implications of the treatment on the developing CNS, all patients&#xD;
             must be ≥ 12 years of age and ≤ 21 years of age at the time of entry into the study.&#xD;
&#xD;
          -  The patient must have a Lansky or Karnofsky Performance Score (KPS) of ≥ 70% at the&#xD;
             time of entry.&#xD;
&#xD;
          -  Laboratory Studies:&#xD;
&#xD;
               1. Platelet count ≥ 125,000 per microliter prior to biopsy. Platelets ≥ 100,000 per&#xD;
                  microliter prior to infusion;&#xD;
&#xD;
               2. Prothrombin and Activated Partial Thromboplastin Times ≤ 1.2 x upper limit of&#xD;
                  normal (ULN) prior to biopsy;&#xD;
&#xD;
               3. Positive serum anti-poliovirus titer ≥ 1:8 prior to biopsy;&#xD;
&#xD;
               4. Creatinine ≤ 1.2 x ULN prior to biopsy;&#xD;
&#xD;
               5. Total bilirubin, AST, ALT, alkaline phosphatase ≤ 2.5 x ULN prior to biopsy;&#xD;
&#xD;
               6. Neutrophil count ≥ 1000 per microliter prior to biopsy;&#xD;
&#xD;
               7. Hemoglobin ≥ 9 gm/dl prior to biopsy (can be transfused).&#xD;
&#xD;
          -  The patient must have received a boost immunization with trivalent inactivated IPOL™&#xD;
             (Sanofi-Pasteur) ≥ 1 week prior to administration of the study agent.&#xD;
&#xD;
          -  At the time of biopsy, prior to administration of virus, the presence of recurrent&#xD;
             tumor must be confirmed by histopathological analysis.&#xD;
&#xD;
          -  A signed informed consent form approved by the Duke University Institutional Review&#xD;
             Board (IRB) will be required for patient enrollment into the study. Patients (if 18&#xD;
             years old) or their parent(s) or guardian(s) must be able to read and understand the&#xD;
             informed consent document and must sign the informed consent indicating that they are&#xD;
             aware of the investigational nature of this study. All children will have to provide&#xD;
             assent to the study.&#xD;
&#xD;
          -  Able to undergo brain MRI with and without contrast without requiring general&#xD;
             anesthesia.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast-feeding. Female patients of child-bearing potential or female&#xD;
             sexual partners (who are of child-bearing potential) of male patients must use at&#xD;
             least one of the following methods of medically acceptable contraceptives: approved&#xD;
             hormonal contraceptives (such as birth control pills, patches, implants or infusions),&#xD;
             an intrauterine device (IUD), or a barrier method of contraception (such as a condom&#xD;
             or diaphragm) used ith spermicide. Because all patients are required to have a boost&#xD;
             immunization of trivalent inactivated IPOL™, there should be no risk of transmission&#xD;
             of a mother to her fetus after receiving intracranial PVSRIPO. As such, patients who&#xD;
             become pregnant after receiving PVSRIPO will continue to be monitored in the same&#xD;
             manner, i.e. per protocol, unless the assessment is contra-indicated during pregnancy.&#xD;
             Partners who become pregnant will sign a Pregnant Partner Information Form and&#xD;
             information regarding the pregnancy and its outcome may be collected.&#xD;
&#xD;
          -  Patients with an impending, life-threatening cerebral herniation syndrome, based on&#xD;
             the assessment of the study neurosurgeon.&#xD;
&#xD;
          -  Patients with an active infection requiring intravenous treatment or having an&#xD;
             unexplained febrile illness (Tmax &gt; 99.5°F).&#xD;
&#xD;
          -  Patients with known immunosuppressive disease or known human immunodeficiency virus&#xD;
             infection.&#xD;
&#xD;
          -  Patients with unstable or severe intercurrent medical conditions such as severe heart&#xD;
             (New York Heart Association Class 3 or 4) or lung (FEV1 &lt; 50%) disease, uncontrolled&#xD;
             diabetes mellitus.&#xD;
&#xD;
          -  Patients with allergy to human serum albumin.&#xD;
&#xD;
          -  Current or history of anaphylactic reaction to gadolinium.&#xD;
&#xD;
          -  A history of neurological complications due to past PV infection would imply previous&#xD;
             virus replication in the CNS. Based on animal studies, previous exposure to poliovirus&#xD;
             administered intracerebrally can reduce subsequent virus replication in the CNS.&#xD;
&#xD;
          -  Patients who have not recovered from the toxic effects of prior chemo- and/or&#xD;
             radiation therapy. Guidelines for this recovery period are dependent upon the specific&#xD;
             therapeutic agent being used:&#xD;
&#xD;
               1. Patients who are less than 12 weeks from radiation therapy, unless progressive&#xD;
                  disease outside of the radiation field or 2 consecutive scans with disease&#xD;
                  progression or histopathologic confirmation of recurrent tumor.&#xD;
&#xD;
               2. Patients who 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 starting the study drug unless patients have&#xD;
                  recovered from side effects of such therapy.&#xD;
&#xD;
               3. Patients who have received immunotherapy ≤ 4 weeks prior to starting the study&#xD;
                  drug unless patients have recovered from side effects of such therapy.&#xD;
&#xD;
          -  Patients with neoplastic lesions in the brainstem, cerebellum, spinal cord,&#xD;
             intraventricular tumors, pituitary tumors, leptomeningeal disease, or other locations&#xD;
             at the discretion of the treating neurosurgeon.&#xD;
&#xD;
          -  Patients with a diagnosis of agammaglobulinemia, that is:&#xD;
&#xD;
               1. Undetectable anti-tetanus toxoid IgG&#xD;
&#xD;
               2. Known history of agammaglobulinemia&#xD;
&#xD;
          -  Patients who are on dexamethasone receiving &gt; 4 mg/day in the two weeks prior to&#xD;
             admission for intra-cerebral delivery of PVSRIPO or who demonstrate worsening steroid&#xD;
             myopathy.&#xD;
&#xD;
          -  Patients with prior, unrelated malignancy requiring current active treatment with the&#xD;
             exception of cervical carcinoma in situ and adequately treated basal cell or squamous&#xD;
             cell carcinoma of the skin.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Darell Bigner, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Istari Oncology, Inc.</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Daniel Landi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Eric Thompson, MD</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>http://www.cancer.duke.edu/btc/</url>
    <description>The Preston Robert Tisch Brain Tumor Center at Duke</description>
  </link>
  <link>
    <url>http://tischbraintumorcenter.duke.edu/pediatrics</url>
    <description>The Preston Robert Tisch Brain Tumor Center at Duke Pediatric Program</description>
  </link>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>February 2, 2017</study_first_submitted>
  <study_first_submitted_qc>February 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 6, 2017</study_first_posted>
  <last_update_submitted>July 12, 2021</last_update_submitted>
  <last_update_submitted_qc>July 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pediatric Malignant Glioma</keyword>
  <keyword>PVSRIPO</keyword>
  <keyword>Pro00071228</keyword>
  <keyword>Eric Thompson</keyword>
  <keyword>Darell Bigner</keyword>
  <keyword>Oncolytic Poliovirus</keyword>
  <keyword>Daniel Landi</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>
    <mesh_term>Ependymoma</mesh_term>
    <mesh_term>Gliosarcoma</mesh_term>
    <mesh_term>Medulloblastoma</mesh_term>
    <mesh_term>Oligodendroglioma</mesh_term>
    <mesh_term>Rhabdoid Tumor</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>June 28, 2022</submitted>
    <returned>May 9, 2023</returned>
    <submitted>June 14, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03043391
org study id: Pro00071228
nct id: NCT03043391
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of the study is to confirm the safety of the selected dose and potential toxicity
      of oncolytic poliovirus (PV) immunotherapy with PVSRIPO for pediatric patients with recurrent
      WHO grade III or IV malignant glioma, but evidence for efficacy will also be sought. The
      primary objective is to confirm the safety of the selected dose of PVSRIPO when delivered
      intracerebrally by convection-enhanced delivery (CED) in children with recurrent WHO Grade
      III malignant glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic
      oligodendroglioma, anaplastic pleomorphic xanthoastrocytoma) or WHO Grade IV malignant glioma
      (glioblastoma, gliosarcoma). A secondary objective is to estimate overall survival (OS) in
      this population.
PVSRIPO will be delivered intratumorally by CED using an intracerebral catheter placed within
      the enhancing portion of the tumor. The population group are patients with recurrent WHO
      grade III or IV malignant glioma who are aged 12 through 21 years old. After a single dose of
      PVSRIPO, subjects will return for periodic visits to monitor tumor status, adverse events,
      and changes in blood immune profiles. A maximum of 12 pediatric patients will be treated with
      PVSRIPO, and then carefully monitored for safety for at least a year after treatment.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Phase Ib study to evaluate feasibility, safety, and preliminary evidence of efficacy of the optimal adult dose in a pediatric population
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of participants with unacceptable toxicity
time frame: 14 days after treatment with PVSRIPO
description: Percentage of participants with unacceptable toxicity during the 14-day period post-PVSRIPO treatment
measure: 24-month overall survival
time frame: 24 months after administration of PVSRIPO
description: The percentage of participants alive at 24 months after the administration of PVSRIPO. Overall survival is defined as the time from the date of administration of PVSRIPO until the date of death, or the date of last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.
arm group label: Polio/Rhinovirus Recombinant (PVSRIPO)
arm group type: Experimental
description: PVSRIPO is an altered form of the live polio vaccine. It was produced by removing a piece of the virus and replacing it with a piece from a common cold virus. This was done to make sure PVSRIPO cannot cause polio even when injected into the brain.
intervention type: Biological
intervention name: Polio/Rhinovirus Recombinant (PVSRIPO)
description: PVSRIPO will be delivered intratumorally by convection-enhanced delivery (CED) using an intracerebral catheter placed within the enhancing portion of the tumor. A stereotactic biopsy will be performed prior to virus administration. Immediately following the stereotactically-guided tumor biopsy, a catheter will be implanted in the operating room at a site the same or different from that used for the biopsy using sterile techniques under general anesthesia. The entire volume of PVSRIPO to be delivered will be pre-loaded into a syringe by the investigational pharmacist and connected to the catheter under sterile conditions in the Pediatric Intensive Care Unit (PICU) just prior to beginning of infusion.
arm group label: Polio/Rhinovirus Recombinant (PVSRIPO)
criteria: 
gender: All
minimum age: 12 Years
maximum age: 21 Years
healthy volunteers: No
last name: Darell Bigner, MD, PhD
role: Study Director
affiliation: Istari Oncology, Inc.
last name: Daniel Landi, MD
role: Principal Investigator
affiliation: Duke University
last name: Eric Thompson, MD
role: Principal Investigator
affiliation: Duke University
facility: 
country: United States
url: http://www.cancer.duke.edu/btc/
description: The Preston Robert Tisch Brain Tumor Center at Duke
url: http://tischbraintumorcenter.duke.edu/pediatrics
description: The Preston Robert Tisch Brain Tumor Center at Duke Pediatric Program
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Glioma
mesh term: Astrocytoma
mesh term: Ependymoma
mesh term: Gliosarcoma
mesh term: Medulloblastoma
mesh term: Oligodendroglioma
mesh term: Rhabdoid Tumor
mesh term: Brain Neoplasms
sharing ipd: No
submitted: June 28, 2022
returned: May 9, 2023
submitted: June 14, 2023