<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/NCT03276676</url>
  </required_header>
  <id_info>
    <org_study_id>HCI104704</org_study_id>
    <nct_id>NCT03276676</nct_id>
  </id_info>
  <brief_title>[18F]Fluciclovine and [18F]FLT PET/CT Assessment of Primary High-Grade Brain Tumors</brief_title>
  <official_title>[18F]Fluciclovine and [18F]FLT PET/CT Assessment of Primary High-Grade Brain Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Blue Earth Diagnostics</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Utah</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 hypothesis of this exploratory clinical trial in patients with high-grade a primary brain&#xD;
      tumor who receive chemoradiation is that the PET imaging agents [18F]Fluciclovine and/or&#xD;
      [18F]FLT will be a better predictor of tumor response than standard MRI based brain tumor&#xD;
      response criteria. When used in conjunction, the two PET agents may be better able to predict&#xD;
      tumor aggressiveness and thus overall survival than the use of individual-tracer PET&#xD;
      biomarkers. This may eventually lead to improved assessment of response (including time to&#xD;
      progression and overall survival) and differentiation of tumor recurrence/progression from&#xD;
      treatment effect (pseudoprogression).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The standard treatment approach for patients with high-grade primary brain tumors includes&#xD;
      maximum feasible surgical resection, followed by 6 weeks of concurrent cranial irradiation,&#xD;
      and daily low-dose temozolomide chemotherapy; followed by 12 cycles of high-dose temozolomide&#xD;
      administered for 5 consecutive days every 4 weeks (Stupp et al., 2005). Contrast-enhanced MRI&#xD;
      is the current standard for evaluating the success of therapy and monitoring for tumor&#xD;
      recurrence. MRI is typically obtained prior to initial surgery, within 24 hours after&#xD;
      surgery, at the conclusions of cranial irradiation, and then every 8 weeks during&#xD;
      temozolomide chemotherapy until evidence of recurrence. Despite this careful clinical and&#xD;
      radiographic surveillance, and despite decades of research into the histologic and molecular&#xD;
      classification of primary brain tumors, our ability to predict tumor behavior remains very&#xD;
      limited. Some gliomas will result in overall survival times of only months, whereas other&#xD;
      histologically-identical gliomas may yield survivals of years to decades (Curran et al.,&#xD;
      1993, Carson et al., 2007). Current assessment of tumor response to therapy is also poor.&#xD;
      Patients with complete radiographic response after cranial irradiation often progress rapidly&#xD;
      post-irradiation. In contrast, some patients with enhancing masses at the end of&#xD;
      chemoradiotherapy may respond dramatically to further chemotherapy alone; or the masses may&#xD;
      even disappear in the absence of further therapy, so called &quot;tumor pseudoprogression&quot;&#xD;
      (Chamberlain et al., 2007). This confounding situation demonstrates a need for better&#xD;
      assessment of tumor response.&#xD;
&#xD;
      Improvements in the ability to predict tumor behavior prior to the start of therapy would&#xD;
      allow more efficient and effective tumor surveillance; better prognostication; and more&#xD;
      appropriate assignment of patients to conventional, aggressive, or investigational therapies&#xD;
      early in their clinical courses. This would provide huge economic and social benefits, and&#xD;
      could afford decisive insights into brain tumor physiology and biology.&#xD;
&#xD;
      Similarly, the ability to identify, earlier and more accurately, whether individual patients&#xD;
      were responding to therapy would allow prompt discontinuation of ineffectual treatments and&#xD;
      institution of potentially more effective therapies.&#xD;
&#xD;
      Previous efforts using imaging for such tasks have generally been limited to a single&#xD;
      modality (e.g. MRI) and/or single-tracer (e.g. FDG-PET). However, there is a significant and&#xD;
      growing body of evidence that complementary imaging of multiple aspects of tumor physiology&#xD;
      (i.e. using multiple PET tracers) can provide greatly enhanced information over imaging with&#xD;
      a single modality or tracer alone. In solid tumors, complex interactions exist between blood&#xD;
      flow, metabolic activity, and oxygen status which affect metastatic and proliferative&#xD;
      activity. Heterogeneous tumors may contain both slow-growing and fast-growing regions that&#xD;
      present different profiles of proliferation rates and amino acid uptake.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 24, 2018</start_date>
  <completion_date type="Anticipated">November 2023</completion_date>
  <primary_completion_date type="Actual">August 20, 2022</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>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Increased Overall Survival</measure>
    <time_frame>2 years</time_frame>
    <description>a 25% reduction in SUVmax (Standardized uptake value) or SUVmean for each of the PET imaging tracers will be predictive of increased overall survival</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Association between overall survival and quantitative markers</measure>
    <time_frame>Within 6 months of chemoradiation</time_frame>
    <description>Assess the association between overall survival and change in each of the following quantitative markers for [18F]Fluciclovine and [18F]FLT: K1-k4, Knet and Ktrans, from baseline to post therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Association between progression free survival and quantitative markers</measure>
    <time_frame>Within 6 months of chemoradiation</time_frame>
    <description>Assess the association between progression free survival and change in each of the following quantitative markers for [18F]Fluciclovine and [18F]FLT: K1-k4, Knet and Ktrans, from baseline to post therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ability of [18F]FLT and/or [18F]Fluciclovine alone or together to predict true progression from pseudoprogression</measure>
    <time_frame>Through study completion, an average of 6 months</time_frame>
    <description>Assess the ability of [18F]FLT and/or [18F]Fluciclovine alone or together to predict true progression from pseudoprogression in patients with this clinical dilemma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>More predictive of overall survival than an MRI</measure>
    <time_frame>2 years</time_frame>
    <description>A 25% reduction in SUVmax or SUVmean for each of the PET imaging tracers will be more predictive of overall survival than the current MRI based response criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>More predictive of time to progression than an MRI</measure>
    <time_frame>2 years</time_frame>
    <description>A 25% reduction in SUVmax or SUVmean for each of the PET imaging tracers will be more predictive of time to progression than the current MRI based response criteria.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Brain Tumor</condition>
  <arm_group>
    <arm_group_label>All Enrolled participants</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Multi-tracer PET exams of [18F]FLT and [18F]Fluciclovine</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Multi-tracer PET exams of [18F]FLT and [18F]Fluciclovine</intervention_name>
    <description>Multi-tracer PET exams of [18F]FLT and [18F]Fluciclovine will be acquired in each patient at up to three time points: (1) prior to any tumor-directed therapy, either prior to surgery or immediately after surgery providing a complete surgical resection was not performed and confirmed by a post-operative contrast MRI scan where residual tumor &gt; 1.0 cm in diameter was present and prior to any tumor-directed therapy; (2) at the conclusions of the initial (~6-8 weeks) chemoradiotherapy; and (3) patients with MRI-documented possible recurrence/progression versus treatment effect (pseudoprogression) within 6 months from the time of completion of chemoradiation.</description>
    <arm_group_label>All Enrolled participants</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Two adult patient groups will be eligible for inclusion in this study:&#xD;
&#xD;
        Group A: Patients where there is compelling evidence, based on the MRI and/or CT imaging,&#xD;
        that a high-grade primary brain tumor is present. Pathologic confirmation will occur with&#xD;
        biopsy or surgery.&#xD;
&#xD;
        Patients whose tumor is felt to be inoperable and a biopsy is performed but no surgery.&#xD;
&#xD;
        Patients with a newly diagnosed primary malignant brain tumor (WHO Grade III or IV) who&#xD;
        will be receiving chemoradiation and who either did not undergo surgical resection or&#xD;
        underwent incomplete resection with residual tumor &gt; 1.0 cm in greatest diameter by&#xD;
        contrast MRI postoperatively.&#xD;
&#xD;
        Group B: Patients with pathologically proven malignant brain tumor (WHO Grade III or IV&#xD;
        glial-based tumors) who have undergone chemoradiation and have MRI-documented possible&#xD;
        recurrence/progression versus treatment effect (pseudoprogression) within 6 months from the&#xD;
        time of completion of chemoradiation.&#xD;
&#xD;
          -  Patients must be 18 years or older for inclusion in this study. There is little&#xD;
             experience with the safety of [18F]FLT or [18F]Fluciclovine in children, and the risks&#xD;
             associated with radiation exposure may be increased for children under 18 years old as&#xD;
             well.&#xD;
&#xD;
          -  Patients must document their willingness to be followed for at least 24 months after&#xD;
             recruitment by signing informed consent documenting their agreement to have clinical&#xD;
             endpoints and the results of histopathologic tissue analysis (when tissue becomes&#xD;
             available from routine care) entered into a research database.&#xD;
&#xD;
          -  All patients, or their legal guardians, must sign a written informed consent and HIPAA&#xD;
             authorization in accordance with institutional guidelines.&#xD;
&#xD;
          -  Determination of pregnancy status: Female patients who are not postmenopausal or&#xD;
             surgically sterile will undergo a serum pregnancy test prior to each set of [18F]FLT&#xD;
             and [18F]Fluciclovine PET scans. A negative test will be necessary for such patients&#xD;
             to undergo research PET imaging.&#xD;
&#xD;
          -  Pre-imaging laboratory tests must be performed within 28 days prior to the [18F]FLT&#xD;
             imaging procedure. These must be less than 4.0 times below or above the upper or lower&#xD;
             limit range for the respective laboratory test for entry into the study (unless&#xD;
             clinically not relevant). In those instances where a laboratory value is outside of&#xD;
             this range, then such a patient will be ineligible for enrollment unless at the&#xD;
             discretion of the PI the abnormal lab value is of no clinical significance to the&#xD;
             safety or integrity of the study results. . For follow-up scanning sessions after&#xD;
             therapy has been instituted, laboratory testing will also be required due to the use&#xD;
             of [18F]FLT. The patients have brain tumors and will have received chemoradiation;&#xD;
             therefore, many routine laboratory tests may not be within the typical normal range.&#xD;
             As such, a factor of 4.0 times above or below the upper or lower value for the normal&#xD;
             range for any laboratory test will also be used to determine the acceptable range for&#xD;
             the 2nd and possibly 3rd imaging time points (unless clinically not relevant as&#xD;
             explained above). The baseline laboratory testing will include liver enzymes (ALT,&#xD;
             AST), bilirubin (total), serum electrolytes, CBC with platelets, prothrombin time,&#xD;
             partial thromboplastin time, BUN, and creatinine. For those patients receiving&#xD;
             coumadin or another anticoagulant the upper limit for prothrombin time or partial&#xD;
             thromboplastin time must not exceed 6 times the upper limit of the normal range.&#xD;
             (Appendix E, Laboratory Study Results).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with clinically significant signs of uncal herniation, such as acute&#xD;
             pupillary enlargement, rapidly developing motor changes (over hours), or rapidly&#xD;
             decreasing level of consciousness, are not eligible.&#xD;
&#xD;
          -  Patients with known allergic or hypersensitivity reactions to previously administered&#xD;
             radiopharmaceuticals. Patients with significant drug or other allergies or autoimmune&#xD;
             diseases may be enrolled at the Investigator's discretion.&#xD;
&#xD;
          -  Patients who are pregnant or lactating or who suspect they might be pregnant. Serum&#xD;
             pregnancy tests will be obtained prior to each set of multi-tracer PET scans in female&#xD;
             patients that are not postmenopausal or surgically sterile.&#xD;
&#xD;
          -  Adult patients who require monitored anesthesia for PET scanning.&#xD;
&#xD;
          -  Patients who are too claustrophobic to undergo PET scanning.&#xD;
&#xD;
          -  Known HIV positive patients due to the previous toxicity noted with [18F]FLT in this&#xD;
             patient group.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John Hoffman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Utah</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Paige Nielsen</last_name>
    <phone>801-585-5942</phone>
    <email>paige.nielsen@hci.utah.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Huntsman Cancer Institute</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paige Nielsen</last_name>
      <phone>801-585-5942</phone>
      <email>paige.nielsen@hci.utah.edu</email>
    </contact>
    <investigator>
      <last_name>John Hoffman, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>September 5, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <disposition_first_submitted>August 17, 2023</disposition_first_submitted>
  <disposition_first_submitted_qc>September 11, 2023</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">September 14, 2023</disposition_first_posted>
  <last_update_submitted>September 11, 2023</last_update_submitted>
  <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 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>Brain Neoplasms</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT03276676
org study id: HCI104704
nct id: NCT03276676
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The hypothesis of this exploratory clinical trial in patients with high-grade a primary brain
      tumor who receive chemoradiation is that the PET imaging agents [18F]Fluciclovine and/or
      [18F]FLT will be a better predictor of tumor response than standard MRI based brain tumor
      response criteria. When used in conjunction, the two PET agents may be better able to predict
      tumor aggressiveness and thus overall survival than the use of individual-tracer PET
      biomarkers. This may eventually lead to improved assessment of response (including time to
      progression and overall survival) and differentiation of tumor recurrence/progression from
      treatment effect (pseudoprogression).
The standard treatment approach for patients with high-grade primary brain tumors includes
      maximum feasible surgical resection, followed by 6 weeks of concurrent cranial irradiation,
      and daily low-dose temozolomide chemotherapy; followed by 12 cycles of high-dose temozolomide
      administered for 5 consecutive days every 4 weeks (Stupp et al., 2005). Contrast-enhanced MRI
      is the current standard for evaluating the success of therapy and monitoring for tumor
      recurrence. MRI is typically obtained prior to initial surgery, within 24 hours after
      surgery, at the conclusions of cranial irradiation, and then every 8 weeks during
      temozolomide chemotherapy until evidence of recurrence. Despite this careful clinical and
      radiographic surveillance, and despite decades of research into the histologic and molecular
      classification of primary brain tumors, our ability to predict tumor behavior remains very
      limited. Some gliomas will result in overall survival times of only months, whereas other
      histologically-identical gliomas may yield survivals of years to decades (Curran et al.,
      1993, Carson et al., 2007). Current assessment of tumor response to therapy is also poor.
      Patients with complete radiographic response after cranial irradiation often progress rapidly
      post-irradiation. In contrast, some patients with enhancing masses at the end of
      chemoradiotherapy may respond dramatically to further chemotherapy alone; or the masses may
      even disappear in the absence of further therapy, so called "tumor pseudoprogression"
      (Chamberlain et al., 2007). This confounding situation demonstrates a need for better
      assessment of tumor response.

      Improvements in the ability to predict tumor behavior prior to the start of therapy would
      allow more efficient and effective tumor surveillance; better prognostication; and more
      appropriate assignment of patients to conventional, aggressive, or investigational therapies
      early in their clinical courses. This would provide huge economic and social benefits, and
      could afford decisive insights into brain tumor physiology and biology.

      Similarly, the ability to identify, earlier and more accurately, whether individual patients
      were responding to therapy would allow prompt discontinuation of ineffectual treatments and
      institution of potentially more effective therapies.

      Previous efforts using imaging for such tasks have generally been limited to a single
      modality (e.g. MRI) and/or single-tracer (e.g. FDG-PET). However, there is a significant and
      growing body of evidence that complementary imaging of multiple aspects of tumor physiology
      (i.e. using multiple PET tracers) can provide greatly enhanced information over imaging with
      a single modality or tracer alone. In solid tumors, complex interactions exist between blood
      flow, metabolic activity, and oxygen status which affect metastatic and proliferative
      activity. Heterogeneous tumors may contain both slow-growing and fast-growing regions that
      present different profiles of proliferation rates and amino acid uptake.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Increased Overall Survival
time frame: 2 years
description: a 25% reduction in SUVmax (Standardized uptake value) or SUVmean for each of the PET imaging tracers will be predictive of increased overall survival
measure: Association between overall survival and quantitative markers
time frame: Within 6 months of chemoradiation
description: Assess the association between overall survival and change in each of the following quantitative markers for [18F]Fluciclovine and [18F]FLT: K1-k4, Knet and Ktrans, from baseline to post therapy.
measure: Association between progression free survival and quantitative markers
time frame: Within 6 months of chemoradiation
description: Assess the association between progression free survival and change in each of the following quantitative markers for [18F]Fluciclovine and [18F]FLT: K1-k4, Knet and Ktrans, from baseline to post therapy.
measure: Ability of [18F]FLT and/or [18F]Fluciclovine alone or together to predict true progression from pseudoprogression
time frame: Through study completion, an average of 6 months
description: Assess the ability of [18F]FLT and/or [18F]Fluciclovine alone or together to predict true progression from pseudoprogression in patients with this clinical dilemma.
measure: More predictive of overall survival than an MRI
time frame: 2 years
description: A 25% reduction in SUVmax or SUVmean for each of the PET imaging tracers will be more predictive of overall survival than the current MRI based response criteria.
measure: More predictive of time to progression than an MRI
time frame: 2 years
description: A 25% reduction in SUVmax or SUVmean for each of the PET imaging tracers will be more predictive of time to progression than the current MRI based response criteria.
arm group label: All Enrolled participants
arm group type: Experimental
description: Multi-tracer PET exams of [18F]FLT and [18F]Fluciclovine
intervention type: Drug
intervention name: Multi-tracer PET exams of [18F]FLT and [18F]Fluciclovine
description: Multi-tracer PET exams of [18F]FLT and [18F]Fluciclovine will be acquired in each patient at up to three time points: (1) prior to any tumor-directed therapy, either prior to surgery or immediately after surgery providing a complete surgical resection was not performed and confirmed by a post-operative contrast MRI scan where residual tumor > 1.0 cm in diameter was present and prior to any tumor-directed therapy; (2) at the conclusions of the initial (~6-8 weeks) chemoradiotherapy; and (3) patients with MRI-documented possible recurrence/progression versus treatment effect (pseudoprogression) within 6 months from the time of completion of chemoradiation.
arm group label: All Enrolled participants
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: John Hoffman, MD
role: Principal Investigator
affiliation: University of Utah
last name: Paige Nielsen
phone: 801-585-5942
email: paige.nielsen@hci.utah.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Brain Neoplasms