<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/NCT03242993</url>
  </required_header>
  <id_info>
    <org_study_id>PET - FOL - I</org_study_id>
    <nct_id>NCT03242993</nct_id>
  </id_info>
  <brief_title>[18F]-AZAFOL AS POSITRON EMISSION TOMOGRAPHY (PET) TRACER in FR Positive Cancer Imaging</brief_title>
  <official_title>Biodistribution, Tumor Detection, and Radiation Dosimentry of [18F]-AZAFOL as POSITRON EMISSION TOMOGRAPHY (PET) Tracer in Folate Receptor Positive Cancer Imaging</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Lausanne Hospitals</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital, Zürich</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cantonal Hospital of St. Gallen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Lausanne Hospitals</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a clinical trial category C as this is a first in man trial with an unapproved&#xD;
      investigational product. Nevertheless the risk is considered low due to the low dose ≤ 10μg.&#xD;
      No toxicity effects were observed preclinically at a dose &gt;1000 -fold the intended dose.&#xD;
      Open-labeled, non-blinded, non-placebo controlled, multicenter study.&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
      Assessment of biodistribution and FR-specific tumor detection of [18F]- AzaFol as a PET&#xD;
      imaging agent in patients with FR-positive and FR-negative metastatic cancer of the ovaries&#xD;
      or lungs.&#xD;
&#xD;
      Secondary objective:&#xD;
&#xD;
      Calculation of the effective dose to the patient according to the tissue distribution data of&#xD;
      [18F]-AzaFol (Dosimetry)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Human research study using a radiopharmaceutical product to reveal folate receptor (FR)&#xD;
      expression in tumors in patients.&#xD;
&#xD;
      It is known that the FR is overexpressed on a variety of tumor types. FR-positive tumors can&#xD;
      be treated with investigational drugs specifically targeting the FR.&#xD;
&#xD;
      Although the FR-expression status may be determined by immunohistochemical staining of tumor&#xD;
      biopsies there is a need for a non-invasive method to determine the presence of the FR on&#xD;
      primary tumors and metastases in humans. For this purpose a radiopharmaceutical product will&#xD;
      be used as a radiotracer. Positron Emission Tomography (PET) is an imaging method which&#xD;
      allows assessing the distribution of radiotracers (called PET tracer). With this imaging&#xD;
      method it is possible to obtain (semi)quantitative measures of FR-expression on tumors of at&#xD;
      least 4-10 mm diameter in patients.&#xD;
&#xD;
      Such a folate-based radiotracer would be a very helpful tool to non-invasively discriminate&#xD;
      FR-positive (often found in ovarian and NSC-lung cancer) from FR-negative tumors in patients&#xD;
      with cancer disease as this would allow selecting FR-positive patients amenable to&#xD;
      FR-targeted therapies, e.g. folate-targeted antimitotic substances such as EC145&#xD;
      VintafolideTM (Endocyte Inc.) or anti-FR-antibodies such as FarletuzumabTM (Morphotek Inc).&#xD;
&#xD;
      Moreover, [18F]-AzaFol PET could be used for tumor staging and monitoring therapy as well as&#xD;
      for follow-up investigations of patients with FR-positive tumors.&#xD;
&#xD;
      Currently there is a radiopharmaceutical product for research purposes available (99mTc-EC20,&#xD;
      EtarfolatideTM, Endocyte Inc.) which can be used for Single Photon Emission Computed&#xD;
      Tomography (SPECT) imaging. SPECT, however, has multiple limitations compared to PET, such as&#xD;
      inferior spatial resolution, soft tissue attenuation, lack of dynamic acquisition etc.&#xD;
      Therefore, a PET-compound for FR imaging has been shown to image FR-positive tumors in&#xD;
      experimental animals .&#xD;
&#xD;
      Calculations regarding the incidence and mortality of six frequent cancer types in&#xD;
      Switzerland indicate that in over 53% of the new cases the FR is expressed (OncoSuisse,&#xD;
      Cancer Statistics 2012).&#xD;
&#xD;
      Investigators demonstrate impressively why FR-targeting emerged as an attractive strategy for&#xD;
      tumor diagnosis and for the development of new targeted therapy strategies .&#xD;
&#xD;
      The vitamin folic acid (pteroylglutamic acid) emerged as an almost ideal FR-targeting agent&#xD;
      because of the high affine binding to the FR (KD &lt; 1 nM).&#xD;
&#xD;
      Due to the small size and vitamin character of folic acid, it is non-immunogenic and&#xD;
      non-toxic.&#xD;
&#xD;
      In spite of a large number of folate-based nuclear imaging agents which have been developed&#xD;
      in the last two decades only one SPECT radiotracer (99mTc-EC20, EtarfolatideTM) is currently&#xD;
      being used in clinical trials in the U.S. for SPECT imaging. For over a decade investigators&#xD;
      have been focusing research activities on the development of a 18F-based folate radiotracer&#xD;
      for PET imaging (13-16). Recently, a novel folate radiotracer has been developed,&#xD;
      3'-aza-3-[18F]fluorofolic acid (herein referred to as [18F]-AzaFol), for PET imaging&#xD;
      purposes.&#xD;
&#xD;
      Compared to SPECT, PET is the more sensitive nuclear imaging method which provides images of&#xD;
      an improved resolution and the possibility for accurate quantification of accumulated&#xD;
      radioactivity in tumor lesions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 1, 2017</start_date>
  <completion_date type="Actual">June 1, 2019</completion_date>
  <primary_completion_date type="Actual">June 1, 2019</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>This is a single arm study. No placebo or other comparator will be used. [18F]-AzaFol is used as a PET tracer, all patients successfully enrolled will be assigned to the treatment group.</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>SUV values and volume of tracer uptake of all suspected positive lesions</measure>
    <time_frame>day 0</time_frame>
    <description>SUVmax g/ml SUVmean42% g/ml&#xD;
lesion seen on SOC : mm</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Potential change of overall staging</measure>
    <time_frame>day 0</time_frame>
    <description>TNM staging</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Lesion detection rate in comparison to SOC (CT and/or MR and/or FDG performed within 4 weeks of PET imaging).</measure>
    <time_frame>day 0</time_frame>
    <description>% (percentage)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Estimation of gained information using this tracer</measure>
    <time_frame>day 0</time_frame>
    <description>uptake yes / no</description>
  </primary_outcome>
  <primary_outcome>
    <measure>quantitative estimations</measure>
    <time_frame>day 0</time_frame>
    <description>SUV values for ROC analysis g/ml</description>
  </primary_outcome>
  <primary_outcome>
    <measure>General estimation of gained confidence in changing/adapting therapy based on this image</measure>
    <time_frame>day 0</time_frame>
    <description>continuous % variable of confidence</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Available biopsy results can be used as further variables to better assess the performance of [18F]-AzaFol</measure>
    <time_frame>day 0</time_frame>
    <description>+ / - ( positive or negative)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Calculation of the effective dose to the patient according to the tissue distribution data of [18F]-AzaFol (Dosimetry)</measure>
    <time_frame>day 0</time_frame>
    <description>The secondary outcome is the calculated tissue distribution data of [18F]-AzaFol obtained in humans. The effective dose for all organs will be calculated using the OLINDA software (version 1.0). The data will be compared to the estimated data from our preclinical data set. This will provide the radiation dosimetry values as well as quantitative biodistribution over all relevant organs.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Metastatic Cancer Lung</condition>
  <condition>Metastatic Ovarian Cancer</condition>
  <arm_group>
    <arm_group_label>treatment group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>all patients successfully enrolled will be assigned to the treatment group:&#xD;
1 mg folic acid (corresponding to 0.2 mL Folarell®) will be injected 5 min prior to [18F]-AzaFol</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>[18F]-AzaFol</intervention_name>
    <description>[18F]-AzaFol is a radiotracer produced at ETH Hönggerberg in a radiopharmaceutical GMP facility. The drug product is provided as sterile solution for intravenous injection in a glass vial containing 6 mL of formulated product, the maximal applicable dose being 600 MBq.</description>
    <arm_group_label>treatment group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>folarell</intervention_name>
    <description>For the purpose of this study only 1 mg folic acid (corresponding to 0.2 mL Folarell®) will be injected 5 min prior to [18F]-AzaFol. Due to this low dose of a single injection of folic acid it is unlikely that adverse events would occur.&#xD;
Folarell® is a folic acid preparation for intravenous or intramuscular injection</description>
    <arm_group_label>treatment group</arm_group_label>
    <other_name>folic acid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with cancer of the ovaries (adenocarcinoma) or non-small cell lung cancer&#xD;
             (adenocarcinoma, squameous cell cancer or other histology) having active tumor with an&#xD;
             indication for a systemic treatment in first or further line.&#xD;
&#xD;
          -  Last systemic treatment should not applied within 3 weeks before performing study exam&#xD;
&#xD;
          -  Male and female patients 18 years and older,&#xD;
&#xD;
          -  Voluntarily signed Informed Consent after being informed&#xD;
&#xD;
        Inclusion criteria for [18F]-AzaFol PET (enrollment into study):&#xD;
&#xD;
          -  FR-positive histology in routinely acquired biopsy samples (30 Patients)&#xD;
&#xD;
          -  FR-negative histology in routinely acquired biopsy samples (6 Patients)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  contraindications to the class of drugs under study, e.g. known hypersensitivity or&#xD;
             allergy to class of drugs or the investigational product,&#xD;
&#xD;
          -  women who are pregnant or breast feeding,&#xD;
&#xD;
          -  women with the intention to become pregnant during the course of the study,&#xD;
&#xD;
          -  other clinically significant concomitant disease states (e.g., renal failure, hepatic&#xD;
             dysfunction, cardiovascular disease),&#xD;
&#xD;
          -  Renal clearance &lt; 60 mL/min; liver transaminases ≥ 3-fold increased; bilirubin &gt;&#xD;
             1.5-fold increased; Hb &lt; 8 g/dl; Tc &lt; 100'000, ANC &lt; 1'500/ul&#xD;
&#xD;
          -  ECOG 3-4&#xD;
&#xD;
          -  known or suspected non-compliance, drug or alcohol abuse,&#xD;
&#xD;
          -  inability to follow the procedures of the study, e.g. due to language problems,&#xD;
             psychological disorders, dementia, etc. of the subject,&#xD;
&#xD;
          -  Participation in another study with an investigational drug during the present study&#xD;
             and 7 days thereafter.&#xD;
&#xD;
          -  Enrolment of the investigator, his family members, employees and other dependent&#xD;
             persons&#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 Prior, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lausanne University Hospitals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lausanne University Hospitals</name>
      <address>
        <city>Lausanne</city>
        <state>Vaud</state>
        <zip>1011</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>July 20, 2017</study_first_submitted>
  <study_first_submitted_qc>August 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 8, 2017</study_first_posted>
  <last_update_submitted>February 27, 2020</last_update_submitted>
  <last_update_submitted_qc>February 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 28, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Lausanne Hospitals</investigator_affiliation>
    <investigator_full_name>Niklaus Schaefer</investigator_full_name>
    <investigator_title>clinical professor</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Folic Acid</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/NCT03242993
org study id: PET - FOL - I
nct id: NCT03242993
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a clinical trial category C as this is a first in man trial with an unapproved
      investigational product. Nevertheless the risk is considered low due to the low dose ≤ 10μg.
      No toxicity effects were observed preclinically at a dose >1000 -fold the intended dose.
      Open-labeled, non-blinded, non-placebo controlled, multicenter study.

      Primary objective:

      Assessment of biodistribution and FR-specific tumor detection of [18F]- AzaFol as a PET
      imaging agent in patients with FR-positive and FR-negative metastatic cancer of the ovaries
      or lungs.

      Secondary objective:

      Calculation of the effective dose to the patient according to the tissue distribution data of
      [18F]-AzaFol (Dosimetry)
Human research study using a radiopharmaceutical product to reveal folate receptor (FR)
      expression in tumors in patients.

      It is known that the FR is overexpressed on a variety of tumor types. FR-positive tumors can
      be treated with investigational drugs specifically targeting the FR.

      Although the FR-expression status may be determined by immunohistochemical staining of tumor
      biopsies there is a need for a non-invasive method to determine the presence of the FR on
      primary tumors and metastases in humans. For this purpose a radiopharmaceutical product will
      be used as a radiotracer. Positron Emission Tomography (PET) is an imaging method which
      allows assessing the distribution of radiotracers (called PET tracer). With this imaging
      method it is possible to obtain (semi)quantitative measures of FR-expression on tumors of at
      least 4-10 mm diameter in patients.

      Such a folate-based radiotracer would be a very helpful tool to non-invasively discriminate
      FR-positive (often found in ovarian and NSC-lung cancer) from FR-negative tumors in patients
      with cancer disease as this would allow selecting FR-positive patients amenable to
      FR-targeted therapies, e.g. folate-targeted antimitotic substances such as EC145
      VintafolideTM (Endocyte Inc.) or anti-FR-antibodies such as FarletuzumabTM (Morphotek Inc).

      Moreover, [18F]-AzaFol PET could be used for tumor staging and monitoring therapy as well as
      for follow-up investigations of patients with FR-positive tumors.

      Currently there is a radiopharmaceutical product for research purposes available (99mTc-EC20,
      EtarfolatideTM, Endocyte Inc.) which can be used for Single Photon Emission Computed
      Tomography (SPECT) imaging. SPECT, however, has multiple limitations compared to PET, such as
      inferior spatial resolution, soft tissue attenuation, lack of dynamic acquisition etc.
      Therefore, a PET-compound for FR imaging has been shown to image FR-positive tumors in
      experimental animals .

      Calculations regarding the incidence and mortality of six frequent cancer types in
      Switzerland indicate that in over 53% of the new cases the FR is expressed (OncoSuisse,
      Cancer Statistics 2012).

      Investigators demonstrate impressively why FR-targeting emerged as an attractive strategy for
      tumor diagnosis and for the development of new targeted therapy strategies .

      The vitamin folic acid (pteroylglutamic acid) emerged as an almost ideal FR-targeting agent
      because of the high affine binding to the FR (KD < 1 nM).

      Due to the small size and vitamin character of folic acid, it is non-immunogenic and
      non-toxic.

      In spite of a large number of folate-based nuclear imaging agents which have been developed
      in the last two decades only one SPECT radiotracer (99mTc-EC20, EtarfolatideTM) is currently
      being used in clinical trials in the U.S. for SPECT imaging. For over a decade investigators
      have been focusing research activities on the development of a 18F-based folate radiotracer
      for PET imaging (13-16). Recently, a novel folate radiotracer has been developed,
      3'-aza-3-[18F]fluorofolic acid (herein referred to as [18F]-AzaFol), for PET imaging
      purposes.

      Compared to SPECT, PET is the more sensitive nuclear imaging method which provides images of
      an improved resolution and the possibility for accurate quantification of accumulated
      radioactivity in tumor lesions.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a single arm study. No placebo or other comparator will be used. [18F]-AzaFol is used as a PET tracer, all patients successfully enrolled will be assigned to the treatment group.
primary purpose: Diagnostic
masking: None (Open Label)
measure: SUV values and volume of tracer uptake of all suspected positive lesions
time frame: day 0
description: SUVmax g/ml SUVmean42% g/ml
lesion seen on SOC : mm
measure: Potential change of overall staging
time frame: day 0
description: TNM staging
measure: Lesion detection rate in comparison to SOC (CT and/or MR and/or FDG performed within 4 weeks of PET imaging).
time frame: day 0
description: % (percentage)
measure: Estimation of gained information using this tracer
time frame: day 0
description: uptake yes / no
measure: quantitative estimations
time frame: day 0
description: SUV values for ROC analysis g/ml
measure: General estimation of gained confidence in changing/adapting therapy based on this image
time frame: day 0
description: continuous % variable of confidence
measure: Available biopsy results can be used as further variables to better assess the performance of [18F]-AzaFol
time frame: day 0
description: + / - ( positive or negative)
measure: Calculation of the effective dose to the patient according to the tissue distribution data of [18F]-AzaFol (Dosimetry)
time frame: day 0
description: The secondary outcome is the calculated tissue distribution data of [18F]-AzaFol obtained in humans. The effective dose for all organs will be calculated using the OLINDA software (version 1.0). The data will be compared to the estimated data from our preclinical data set. This will provide the radiation dosimetry values as well as quantitative biodistribution over all relevant organs.
arm group label: treatment group
arm group type: Experimental
description: all patients successfully enrolled will be assigned to the treatment group:
1 mg folic acid (corresponding to 0.2 mL Folarell®) will be injected 5 min prior to [18F]-AzaFol
intervention type: Drug
intervention name: [18F]-AzaFol
description: [18F]-AzaFol is a radiotracer produced at ETH Hönggerberg in a radiopharmaceutical GMP facility. The drug product is provided as sterile solution for intravenous injection in a glass vial containing 6 mL of formulated product, the maximal applicable dose being 600 MBq.
arm group label: treatment group
intervention type: Drug
intervention name: folarell
description: For the purpose of this study only 1 mg folic acid (corresponding to 0.2 mL Folarell®) will be injected 5 min prior to [18F]-AzaFol. Due to this low dose of a single injection of folic acid it is unlikely that adverse events would occur.
Folarell® is a folic acid preparation for intravenous or intramuscular injection
arm group label: treatment group
other name: folic acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: John Prior, Prof
role: Principal Investigator
affiliation: Lausanne University Hospitals
facility: 
country: Switzerland
responsible party type: Principal Investigator
investigator affiliation: University of Lausanne Hospitals
investigator full name: Niklaus Schaefer
investigator title: clinical professor
mesh term: Folic Acid