<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/NCT03811886</url>
  </required_header>
  <id_info>
    <org_study_id>CASE1718</org_study_id>
    <nct_id>NCT03811886</nct_id>
  </id_info>
  <brief_title>Natalizumab in Recurrent, Refractory or Progressive Pulmonary Metastatic Osteosarcoma</brief_title>
  <official_title>A Phase I/II Study of Natalizumab as a Single Agent in Children, Adolescents and Young Adults With Recurrent, Refractory or Progressive Pulmonary Metastatic Osteosarcoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Case Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Case Comprehensive Cancer Center</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and tolerability of Natalizumab in&#xD;
      children, adolescent and young adult patients with pulmonary metastatic osteosarcoma (pOS)&#xD;
      and to assess clinical response associated with this treatment as well as overall survival.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a single-arm, open-label, proof of concept clinical trial in children,&#xD;
      adolescent and young adult patients with unresectable pOS that have progressed, relapsed or&#xD;
      are refractory to standard systemic therapy.&#xD;
&#xD;
      All participants will receive the study therapy and there will be dose escalation in a&#xD;
      traditional 3 + 3 design during the Phase I study of this trial.&#xD;
&#xD;
      In the Phase II study of the trial, treatment will continue if the subject has Complete&#xD;
      Response (CR), Partial Response (PR) or Stable Disease (SD) of pOS after every 3 cycles after&#xD;
      the first 6 cycles but not beyond 24 cycles, unless it is judged to be in his/her best&#xD;
      interest.&#xD;
&#xD;
      Approximately 3-9 subjects will be enrolled in the phase I part and 10-12 in the phase II&#xD;
      part of this trial. Participants will be followed for toxicity for 30 days after treatment&#xD;
      has been discontinued or until one of the protocol-defined reasons&#xD;
&#xD;
      This study seeks to evaluate if Natalizumab can be used safely and effectively as&#xD;
      immunotherapy in children, adolescent and young adult patients with pOS. Natalizumab is&#xD;
      currently Food and Drug Administration (FDA) approved for the treatment of T-cell mediated&#xD;
      autoimmune disorders The study team will evaluate the safety and tolerability of Natalizumab&#xD;
      as well as the clinical response associated with Natalizumab treatment and evaluate overall&#xD;
      survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Anticipated">October 1, 2023</start_date>
  <completion_date type="Anticipated">October 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2023</primary_completion_date>
  <phase>Phase 1/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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dosing limiting toxicity</measure>
    <time_frame>30 days after end of treatment (1 year)</time_frame>
    <description>Hematologic dose limiting toxicities: Grade 4 neutropenia or thrombocytopenia of &gt; 7 days duration; or myelosuppression that causes a delay of &gt; 8 weeks between treatment courses&#xD;
Non-hematologic dose-limiting toxicities: Any Grade 4 non-hematologic toxicity attributable to Natalizumab with the specific exclusion of:&#xD;
Grade 4 nausea and vomiting responding to anti-emetics, alopecia, fatigue and drug related fever&#xD;
Grade 4 fever&#xD;
Any Grade 3 or greater neurologic toxicity&#xD;
Any Grade 3 or greater anaphylaxis&#xD;
Any Grade 2 or greater elevation in transaminases and bilirubin levels&#xD;
Any Grade 4 non-hematologic toxicities (excluding alopecia, nausea and vomiting) that do not resolve to ≤ Grade 1 by 8 weeks following the most recent dose of Natalizumab</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical benefit rate</measure>
    <time_frame>1 year after start of treatment</time_frame>
    <description>Clinical benefit rate as defined by the number of participants that have Complete Response (CR), Partial Response (PR) or Stable Disease (SD) after 12 cycles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival measured in months</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Overall survival measured in months and summarized using Kaplan-Meier analysis. This will be calculated from the date of registration on-study to the dates of documented evidence of progression or death, up to 3 years</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Pulmonary Metastatic Osteosarcoma (pOS)</condition>
  <arm_group>
    <arm_group_label>Phase I: Natalizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Traditional 3+3 design escalation of Natalizumab at a weight-based dosing 2mg/kg not to exceed a maximum dose of 300mg&#xD;
Phase II treatment to continue if the participant has Complete Response (CR), Partial Response (PR) or Stable Disease (SD) of pOS as defined by RECIST 1.1 criteria after every 3 cycles after the first 6 cycles but not beyond 24 cycles. If the participant has progressive disease after 6 cycles, they will be removed from the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Natalizumab</intervention_name>
    <description>Natalizumab is an FDA approved monotherapy for treatment of relapsing forms of MS. It is also indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active CD who have had an inadequate response to, or intolerance of, conventional therapies and TNF-α inhibitors.&#xD;
Traditional 3+3 escalation of Natalizumab at a weight-based dosing 2mg/kg not to exceed 300mg. If no subjects experience a dose limiting toxicity (DLT), 3 more subjects are enrolled at the next dose of 3mg/kg, not to exceed 300mg. If no subjects experience a DLT, 3 more subjects will be enrolled at the next and final dose of 4mg/kg, not to exceed 300mg.&#xD;
Phase II will continue if the subject has Complete Response (CR), Partial Response (PR) or Stable Disease (SD) of pOS, defined by RECIST 1.1 criteria after every 3 cycles after the first 6 cycles but not beyond 24 cycles. If subject has progressive disease after cycle 6, they will be removed from the study.</description>
    <arm_group_label>Phase I: Natalizumab</arm_group_label>
    <other_name>Tysabri</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must have histologic verification of pOS.&#xD;
&#xD;
          -  Subjects must have measurable pulmonary disease per RECIST 1.1 documented by clinical,&#xD;
             radiographic and histologic criteria, and have progressed, relapsed or become&#xD;
             refractory to conventional therapy.&#xD;
&#xD;
          -  Subjects must have recovered from the acute toxic effects with ≤ Grade 1 as defined by&#xD;
             the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CASE&#xD;
             1718 Page 20 Version date: 9/11/18 CTCAE) Version 5.0 of all prior chemotherapy and&#xD;
             immunotherapy with the exception of alopecia, anorexia, bone pain, and tumor pain&#xD;
             prior to entering this study.&#xD;
&#xD;
          -  Myelosuppressive chemotherapy: Must have adequate recovery of counts from previous&#xD;
             treatment prior to entry onto this study.&#xD;
&#xD;
          -  Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy&#xD;
             that included a monoclonal antibody.&#xD;
&#xD;
          -  Subjects must have a performance status corresponding to a Karnofsky ≥ 50% for&#xD;
             participants &gt; 16 years of age and Lansky ≥ 60 for participants ≤ 16 years of age.&#xD;
             Participants who are unable to walk because of paralysis, but who are up in a&#xD;
             wheelchair will be considered ambulatory for the purpose of assessing the performance&#xD;
             score.&#xD;
&#xD;
          -  Subjects must have normal organ and marrow function as defined below:&#xD;
&#xD;
          -  Adequate bone marrow function defined as:&#xD;
&#xD;
          -  Peripheral absolute neutrophil count (ANC) ≥ 750/mcL&#xD;
&#xD;
          -  Platelet count ≥ 75,000/mcL (transfusion independent)&#xD;
&#xD;
          -  Hemoglobin ≥ 8.0 g/dL (may receive packed red blood cell transfusions)&#xD;
&#xD;
          -  Adequate liver function defined as:&#xD;
&#xD;
          -  Total bilirubin ≤ 1.5 times the upper limit of normal for age&#xD;
&#xD;
          -  AST (SGOT) and ALT (SGPT) 2.5 X institutional upper limit of normal&#xD;
&#xD;
          -  Serum albumin &gt; 2 g/dL&#xD;
&#xD;
          -  Adequate cardiac function defined as:&#xD;
&#xD;
          -  Ejection fraction of ≥ 50% by echocardiogram&#xD;
&#xD;
          -  Subjects must have the ability to understand and the willingness to sign a written&#xD;
             informed consent document if ≥ 18 years of age and an assent document if &lt; 18 years of&#xD;
             age. If &lt; 7 years of age, no assent document is required.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        The presence of any of the following will exclude a subject from study enrollment.&#xD;
&#xD;
          -  Ongoing prior treatment toxicities &gt; Grade 1 according to NCI CTCAE Version 5.0 with&#xD;
             the exception of alopecia, anorexia, bone pain and tumor pain.&#xD;
&#xD;
          -  Subjects receiving any other investigational agents.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to Natalizumab.&#xD;
&#xD;
          -  Subjects currently on immunosuppressive therapy.&#xD;
&#xD;
          -  Subjects with uncontrolled intercurrent illness including, but not limited to ongoing&#xD;
             or active infection, liver failure, symptomatic congestive heart failure, unstable&#xD;
             angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that&#xD;
             would limit compliance with study requirements.&#xD;
&#xD;
          -  Pregnant or breastfeeding women are excluded from this study because Natalizumab&#xD;
             crosses the placenta and can increase the risk of spontaneous abortion. There is an&#xD;
             unknown, but potential risk for adverse events in nursing infants secondary to&#xD;
             treatment of the mother with Natalizumab, therefore breastfeeding should be&#xD;
             discontinued if the mother is treated with Natalizumab.&#xD;
&#xD;
          -  Female participants of childbearing potential are not eligible unless a negative&#xD;
             pregnancy test result has been obtained.&#xD;
&#xD;
          -  Women of childbearing potential and men must agree to use adequate contraception prior&#xD;
             to study entry and for the duration of study participation. Should a woman become&#xD;
             pregnant or suspect she is pregnant while participating in this study, she should&#xD;
             inform her treating physician immediately.&#xD;
&#xD;
          -  HIV-positive subjects and HIV-positive subjects on antiretroviral therapy are&#xD;
             ineligible because of the risk for developing a lethal infection when treated with&#xD;
             immunosuppressive therapy.&#xD;
&#xD;
          -  Participants who have or have had progressive multifocal leukoencephalopathy (PML).&#xD;
&#xD;
          -  Participants whose pulmonary metastatic disease can be completely surgically resected.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kristen VanHeyst, DO</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospitals Cleveland Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kristen VanHeyst, DO</last_name>
    <phone>216-844-3345</phone>
    <email>PHOCTU@UHhospitals.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kristen VanHeyst, DO</last_name>
      <phone>216-844-3345</phone>
      <email>PHOCTU@UHhospitals.org</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 18, 2019</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <last_update_submitted>June 26, 2023</last_update_submitted>
  <last_update_submitted_qc>June 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Natalizumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteosarcoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Natalizumab</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/NCT03811886
org study id: CASE1718
nct id: NCT03811886
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of this study is to evaluate the safety and tolerability of Natalizumab in
      children, adolescent and young adult patients with pulmonary metastatic osteosarcoma (pOS)
      and to assess clinical response associated with this treatment as well as overall survival.
This study is a single-arm, open-label, proof of concept clinical trial in children,
      adolescent and young adult patients with unresectable pOS that have progressed, relapsed or
      are refractory to standard systemic therapy.

      All participants will receive the study therapy and there will be dose escalation in a
      traditional 3 + 3 design during the Phase I study of this trial.

      In the Phase II study of the trial, treatment will continue if the subject has Complete
      Response (CR), Partial Response (PR) or Stable Disease (SD) of pOS after every 3 cycles after
      the first 6 cycles but not beyond 24 cycles, unless it is judged to be in his/her best
      interest.

      Approximately 3-9 subjects will be enrolled in the phase I part and 10-12 in the phase II
      part of this trial. Participants will be followed for toxicity for 30 days after treatment
      has been discontinued or until one of the protocol-defined reasons

      This study seeks to evaluate if Natalizumab can be used safely and effectively as
      immunotherapy in children, adolescent and young adult patients with pOS. Natalizumab is
      currently Food and Drug Administration (FDA) approved for the treatment of T-cell mediated
      autoimmune disorders The study team will evaluate the safety and tolerability of Natalizumab
      as well as the clinical response associated with Natalizumab treatment and evaluate overall
      survival.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dosing limiting toxicity
time frame: 30 days after end of treatment (1 year)
description: Hematologic dose limiting toxicities: Grade 4 neutropenia or thrombocytopenia of > 7 days duration; or myelosuppression that causes a delay of > 8 weeks between treatment courses
Non-hematologic dose-limiting toxicities: Any Grade 4 non-hematologic toxicity attributable to Natalizumab with the specific exclusion of:
Grade 4 nausea and vomiting responding to anti-emetics, alopecia, fatigue and drug related fever
Grade 4 fever
Any Grade 3 or greater neurologic toxicity
Any Grade 3 or greater anaphylaxis
Any Grade 2 or greater elevation in transaminases and bilirubin levels
Any Grade 4 non-hematologic toxicities (excluding alopecia, nausea and vomiting) that do not resolve to ≤ Grade 1 by 8 weeks following the most recent dose of Natalizumab
measure: Clinical benefit rate
time frame: 1 year after start of treatment
description: Clinical benefit rate as defined by the number of participants that have Complete Response (CR), Partial Response (PR) or Stable Disease (SD) after 12 cycles
measure: Overall survival measured in months
time frame: Up to 3 years
description: Overall survival measured in months and summarized using Kaplan-Meier analysis. This will be calculated from the date of registration on-study to the dates of documented evidence of progression or death, up to 3 years
arm group label: Phase I: Natalizumab
arm group type: Experimental
description: Traditional 3+3 design escalation of Natalizumab at a weight-based dosing 2mg/kg not to exceed a maximum dose of 300mg
Phase II treatment to continue if the participant has Complete Response (CR), Partial Response (PR) or Stable Disease (SD) of pOS as defined by RECIST 1.1 criteria after every 3 cycles after the first 6 cycles but not beyond 24 cycles. If the participant has progressive disease after 6 cycles, they will be removed from the study.
intervention type: Drug
intervention name: Natalizumab
description: Natalizumab is an FDA approved monotherapy for treatment of relapsing forms of MS. It is also indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active CD who have had an inadequate response to, or intolerance of, conventional therapies and TNF-α inhibitors.
Traditional 3+3 escalation of Natalizumab at a weight-based dosing 2mg/kg not to exceed 300mg. If no subjects experience a dose limiting toxicity (DLT), 3 more subjects are enrolled at the next dose of 3mg/kg, not to exceed 300mg. If no subjects experience a DLT, 3 more subjects will be enrolled at the next and final dose of 4mg/kg, not to exceed 300mg.
Phase II will continue if the subject has Complete Response (CR), Partial Response (PR) or Stable Disease (SD) of pOS, defined by RECIST 1.1 criteria after every 3 cycles after the first 6 cycles but not beyond 24 cycles. If subject has progressive disease after cycle 6, they will be removed from the study.
arm group label: Phase I: Natalizumab
other name: Tysabri
criteria: 
gender: All
minimum age: 5 Years
maximum age: 30 Years
healthy volunteers: No
last name: Kristen VanHeyst, DO
role: Principal Investigator
affiliation: University Hospitals Cleveland Medical Center
last name: Kristen VanHeyst, DO
phone: 216-844-3345
email: PHOCTU@UHhospitals.org
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Sponsor
mesh term: Osteosarcoma
mesh term: Natalizumab