<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/NCT02992015</url>
  </required_header>
  <id_info>
    <org_study_id>15-1621.cc</org_study_id>
    <nct_id>NCT02992015</nct_id>
  </id_info>
  <brief_title>Gemcitabine in Newly-Diagnosed Diffuse Intrinsic Pontine Glioma</brief_title>
  <official_title>A Clinical Trial Trial of Gemcitabine in Children With Newly-Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Children's Hospital Colorado</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Colorado, Denver</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive childhood brain tumor that, despite&#xD;
      many past clinical trials, has never been shown to respond to chemotherapy. Radiation therapy&#xD;
      (RT) is effective in extending life but is not curative; median overall survival is 11&#xD;
      months. It is still unclear why the hundreds of clinical trials involving chemotherapy of&#xD;
      DIPG have failed to demonstrate any activity against the tumor. Given that many agents tried&#xD;
      in clinical trials cross the blood brain barrier (BBB), it is possible that there are factors&#xD;
      specific to DIPG and its location that prevent adequate drug penetration. Gemcitabine has&#xD;
      been selected for this study because there is strong evidence of DIPG cell line inhibition in&#xD;
      vitro and good BBB penetration. Furthermore, pediatric dosing and toxicity has been&#xD;
      established in prior studies of children with relapsed solid tumors and leukemia.&#xD;
&#xD;
      The primary aim of this study is to determine the presence of gemcitabine in childhood DIPG&#xD;
      tissue after systemic treatment with the drug. The secondary aim is to quantify the&#xD;
      intratumoral gemcitabine concentration after systemic treatment.&#xD;
&#xD;
      Participants in this study will be given a one time IV dose of gemcitabine prior to having&#xD;
      standard of care surgery. During surgery biopsies will be obtained for clinical and research&#xD;
      purposes along with a blood sample. Because patients will be undergoing this biopsy as part&#xD;
      of their standard of care therapy here at Children's Hospital Colorado, this is an optimal&#xD;
      time to obtain a tumor biopsy for this study. The biopsy will serve to see if the study drug&#xD;
      is penetrating the tumor. Patients will then enter a follow-up period for 30 days post&#xD;
      surgery.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 23, 2016</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PK testing levels of gemcitabine, its metabolite difluorodeoxyuridine (dFdU), and gemcitabine necleotides in peripheral blood and DIPG tissue</measure>
    <time_frame>2-12 hours post systemic admininstration of gemcitabine.</time_frame>
    <description>The investigators will use liquid chromatography/tandem mass spectrometry (LC-MS/MS). An API 4000 instrument will be used, which has an approximate sensitivity of 0.1 ng/mg. Given the dimensions of the biopsy needle used, 10 mm length and 0.75 mm diameter, the investigators expect that each core will have an approximate volume of 4.5 mm2, which translates to a likely mass of 4.5 mg. Given that approximately 10 mg of tumor tissue has been necessary for quantification of gemcitabine and its matabolites in past studies, multiple cores of the six available for quantification from neighboring regions of the tumor may be combined; whenever possible. However, more than one separate measurement of concentrations will be done for each patient to determine any variation in concentrations across the tumor. An internal control measurement for gemcitabine will be determined using a variant gemcitabine compound enriched with 13C (Carbon 13).</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Diffuse Intrinsic Pontine Glioma</condition>
  <arm_group>
    <arm_group_label>Gemcitabine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The entire therapy on this study is one dose of gemcitabine. No intrapatient dose modifications are necessary. Gemcitabine will be given at 2100 mg/m2 IV over 30 minutes within 4 hours of planned surgical procedure.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>Participants receive a one time IV dose of gemcitabine prior to having standard of care surgery.</description>
    <arm_group_label>Gemcitabine</arm_group_label>
    <other_name>Gemzar</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age greater than or equal to 3 years and less than 18 years at the time of enrollment&#xD;
&#xD;
          2. Patients must meet both of the following:&#xD;
&#xD;
               -  Clinical findings consistent with a presumed new diagnosis of DIPG&#xD;
&#xD;
               -  Brain MRI findings consistent with a new diagnosis of DIPG in the opinion of the&#xD;
                  treating pediatric neuro-oncologist and neurosurgeon&#xD;
&#xD;
          3. Organ Function Requirements&#xD;
&#xD;
             Adequate bone marrow function defined as:&#xD;
&#xD;
               -  Platelet count ≥100,000/µl (no platelet transfusion for more than 3 days)&#xD;
&#xD;
               -  Hemoglobin &gt;8 g/dl and absolute neutrophil count (ANC) ≥1,000/µl&#xD;
&#xD;
             Adequate coagulation defined as:&#xD;
&#xD;
               -  Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ upper&#xD;
                  limit of normal (ULN) for age.&#xD;
&#xD;
             Adequate renal function defined as:&#xD;
&#xD;
               -  Creatinine clearane or radioisotope GFR &gt; 70 ml/min/1.73 m2 or&#xD;
&#xD;
               -  Maximum serum creatinine (mg/dL) based on age/gender as follows:&#xD;
&#xD;
                    -  Male 3 to &lt;6 yrs: 0.8 mg/dL&#xD;
&#xD;
                    -  Female 3 to &lt;6 yrs: 0.8 mg/dL&#xD;
&#xD;
                    -  Male 6 to &lt;10 yrs: 1.0 mg/dL&#xD;
&#xD;
                    -  Female 6 to &lt;10 yrs: 1.0 mg/dL&#xD;
&#xD;
                    -  Male 10 to &lt;13 yrs : 1.2 mg/dL&#xD;
&#xD;
                    -  Female 10 to &lt;13 yrs: 1.2 mg/dL&#xD;
&#xD;
                    -  Male 13 to &lt;16 yrs: 1.5 mg/dL&#xD;
&#xD;
                    -  Female 13 to &lt;16 yrs: 1.4 mg/dL&#xD;
&#xD;
                    -  Male 16 to &lt;18 yrs : 1.7 mg/dL&#xD;
&#xD;
                    -  Female 16 to &lt;18 yrs: 1.4 mg/dL&#xD;
&#xD;
             The threshold creatinine values in this Table were derived from the Schwartz formula&#xD;
             for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and&#xD;
             stature data published by the CDC.&#xD;
&#xD;
             Adequate liver function defined as:&#xD;
&#xD;
               -  Total bilirubin &lt;3x ULN for age and SGOT (AST) and SGPT (ALT) &lt;2.5x ULN for age&#xD;
&#xD;
          4. Patients must meet one of the following performance scores:&#xD;
&#xD;
               -  ECOG performance status scores of 0, 1, or 2;&#xD;
&#xD;
               -  Karnofsky score of ≥ 60 for patients &gt; 16 years of age; or&#xD;
&#xD;
               -  Lansky score of ≥ 60 for patients ≤ 16 years of age&#xD;
&#xD;
          5. Pontine tumor biopsy is planned for the clinical care of the patient independent of&#xD;
             study participation by the treating pediatric neurosurgeon and neuro-oncologist.&#xD;
&#xD;
          6. Informed consent and assent obtained as appropriate.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant or breastfeeding patients due to teratogenic effects seen in animal/human&#xD;
             studies.&#xD;
&#xD;
          2. Patients who have received any tumor-directed therapy prior to biopsy. Concurrent&#xD;
             treatment with corticosteroids is allowed.&#xD;
&#xD;
          3. Patients with intratumoral hemorrhage larger than 0.5 cm on preoperative imaging.&#xD;
&#xD;
          4. Patients with personal or family history of bleeding disorders.&#xD;
&#xD;
          5. Patients with uncontrolled intercurrent illness including, but not limited to ongoing&#xD;
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,&#xD;
             cardiac arrhythmia, or psychiatric illness/social situations that would limit&#xD;
             compliance with study requirements.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adam Green, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Colorado, Denver</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Adam Green, MD</last_name>
    <email>adam.green@childrenscolorado.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ashley Mettetal, BA</last_name>
    <email>ashley.mettetal@childrenscolorado.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Children's Hospital Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Adam Green, MD</last_name>
      <email>adam.green@childrenscolorado.org</email>
    </contact>
    <contact_backup>
      <last_name>Ashley Mettetal, BA</last_name>
      <email>ashley.mettetal@childrenscolorado.org</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>November 29, 2016</study_first_submitted>
  <study_first_submitted_qc>December 9, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 14, 2016</study_first_posted>
  <last_update_submitted>February 16, 2023</last_update_submitted>
  <last_update_submitted_qc>February 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Diffuse Intrinsic Pontine Glioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</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/NCT02992015
org study id: 15-1621.cc
nct id: NCT02992015
lead sponsor: 
collaborator: 
has dmc: Yes
Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive childhood brain tumor that, despite
      many past clinical trials, has never been shown to respond to chemotherapy. Radiation therapy
      (RT) is effective in extending life but is not curative; median overall survival is 11
      months. It is still unclear why the hundreds of clinical trials involving chemotherapy of
      DIPG have failed to demonstrate any activity against the tumor. Given that many agents tried
      in clinical trials cross the blood brain barrier (BBB), it is possible that there are factors
      specific to DIPG and its location that prevent adequate drug penetration. Gemcitabine has
      been selected for this study because there is strong evidence of DIPG cell line inhibition in
      vitro and good BBB penetration. Furthermore, pediatric dosing and toxicity has been
      established in prior studies of children with relapsed solid tumors and leukemia.

      The primary aim of this study is to determine the presence of gemcitabine in childhood DIPG
      tissue after systemic treatment with the drug. The secondary aim is to quantify the
      intratumoral gemcitabine concentration after systemic treatment.

      Participants in this study will be given a one time IV dose of gemcitabine prior to having
      standard of care surgery. During surgery biopsies will be obtained for clinical and research
      purposes along with a blood sample. Because patients will be undergoing this biopsy as part
      of their standard of care therapy here at Children's Hospital Colorado, this is an optimal
      time to obtain a tumor biopsy for this study. The biopsy will serve to see if the study drug
      is penetrating the tumor. Patients will then enter a follow-up period for 30 days post
      surgery.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: PK testing levels of gemcitabine, its metabolite difluorodeoxyuridine (dFdU), and gemcitabine necleotides in peripheral blood and DIPG tissue
time frame: 2-12 hours post systemic admininstration of gemcitabine.
description: The investigators will use liquid chromatography/tandem mass spectrometry (LC-MS/MS). An API 4000 instrument will be used, which has an approximate sensitivity of 0.1 ng/mg. Given the dimensions of the biopsy needle used, 10 mm length and 0.75 mm diameter, the investigators expect that each core will have an approximate volume of 4.5 mm2, which translates to a likely mass of 4.5 mg. Given that approximately 10 mg of tumor tissue has been necessary for quantification of gemcitabine and its matabolites in past studies, multiple cores of the six available for quantification from neighboring regions of the tumor may be combined; whenever possible. However, more than one separate measurement of concentrations will be done for each patient to determine any variation in concentrations across the tumor. An internal control measurement for gemcitabine will be determined using a variant gemcitabine compound enriched with 13C (Carbon 13).
arm group label: Gemcitabine
arm group type: Experimental
description: The entire therapy on this study is one dose of gemcitabine. No intrapatient dose modifications are necessary. Gemcitabine will be given at 2100 mg/m2 IV over 30 minutes within 4 hours of planned surgical procedure.
intervention type: Drug
intervention name: Gemcitabine
description: Participants receive a one time IV dose of gemcitabine prior to having standard of care surgery.
arm group label: Gemcitabine
other name: Gemzar
criteria: 
gender: All
minimum age: 3 Years
maximum age: 17 Years
healthy volunteers: No
last name: Adam Green, MD
role: Principal Investigator
affiliation: University of Colorado, Denver
last name: Adam Green, MD
email: adam.green@childrenscolorado.org
last name: Ashley Mettetal, BA
email: ashley.mettetal@childrenscolorado.org
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Sponsor
mesh term: Glioma
mesh term: Diffuse Intrinsic Pontine Glioma
mesh term: Gemcitabine