<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/NCT04504552</url>
  </required_header>
  <id_info>
    <org_study_id>IMPEDE</org_study_id>
    <nct_id>NCT04504552</nct_id>
  </id_info>
  <brief_title>Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions</brief_title>
  <acronym>IMPEDE</acronym>
  <official_title>Phase II Trial, Open Label, Single-arm, of Immune Checkpoint Inhibitor In High Risk Oral Premalignant Lesions</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</source>
  <oversight_info>
    <has_dmc>No</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 trial is designed as a prospective, multi-centre, open-label, single-arm, phase II&#xD;
      study.&#xD;
&#xD;
      Oral Premalignant Lesions (OPL) may be considered the equilibrium phase of the immunoediting&#xD;
      concept, i.e. a dynamic process between the tumour cells and the immune system including&#xD;
      surveillance by the immune system or tumour progression. Thus, an imbalance in&#xD;
      immunosuppressive microenvironment is a possible key in malignant transformation. In this&#xD;
      regard, the activation of the PD-1/PD-L1 pathway has a central role, witnessed by the&#xD;
      expression of PD-L1 by multiple cell types within the microenvironment of OPL&#xD;
      (tumour-associated macrophages, fibroblasts, lymphocytes) and by the fact that PD-L1&#xD;
      expression in epithelial and subepithelial cells is associated with malignant transformation.&#xD;
      The use of checkpoint inhibitors in this setting seems to be justified by this rationale.&#xD;
      Employing intermediate end-point markers during preventive strategies against OPL may allow&#xD;
      the conduction of smaller trials, able to give insights for designing larger studies and to&#xD;
      better select the population receiving benefit from the treatment. In this regard, the&#xD;
      evaluation of phenotypic changes (reduction in size or in grade of dysplasia) may not be&#xD;
      enough to assess the potential benefit of an intervention. Modulation of molecular markers&#xD;
      may be more precise indicator of oral cancer risk in patients with OPL. Thus, the change in&#xD;
      LOH at critical loci may be considered intermediate end-point biomarkers of prevention as&#xD;
      well as predictors of cancer risk at baseline. Previous experience with anti-EGFR agents&#xD;
      showed the feasibility of such measures in a prevention trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OPL represent the most common oral precancerous condition, with a potential of malignant&#xD;
      transformation varying from 1% to 47% in different studies. Among molecular markers, the most&#xD;
      effective in predicting oral cancer risk is loss of heterozygosity (LOH), which may appear in&#xD;
      tissues with different histological grade of dysplasia. Patients carrying OPL with LOH at&#xD;
      3p14 and/or 9p21 plus LOH at another locus have an expected 3-year risk of developing oral&#xD;
      cancer of 35%. This chromosomal profile is found in about 28% of OPL. Moreover, when a&#xD;
      patient has previously suffered from oral cavity cancer, the 3-year risk of malignant&#xD;
      transformation for OPL with such a chromosomal profile reaches 69%. The presence of tumour&#xD;
      suppressor genes (TSGs) at these chromosomal loci explains the potential for cancer&#xD;
      development in the presence of such alterations.&#xD;
&#xD;
      The clinical management of small OPL is excision by a cold knife or laser. However, treatment&#xD;
      is not effective to prevent oral cancer in patients. Lesions recur frequently and transform&#xD;
      subsequently, and tumours develop in the same or adjacent anatomical region. For larger OPL&#xD;
      the clinical management is limited to lifelong surveillance. To improve clinical management&#xD;
      of OPLs, the arsenal of treatments should be expanded.&#xD;
&#xD;
      Therefore, this study is aimed at treating high-risk OPL with a short course of immunotherapy&#xD;
      (avelumab)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 16, 2020</start_date>
  <completion_date type="Anticipated">March 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">October 31, 2023</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recurrence-free survival or malignant transformation-free survival</measure>
    <time_frame>Every 2 weeks for the first 6 months, then every month for 1 year, then every 3 months for 30 months</time_frame>
    <description>Recurrence or malignancy-free survival since immunotherapy start, for which the events of interest are the recurrence of OPL with LOH or malignant transformation of OPL</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in LOH status (positive to negative) of OPL</measure>
    <time_frame>6 months</time_frame>
    <description>Change in LOH status (positive to negative) of OPL after 6 months since the start of immunotherapy. This is defined as disappearance of any high-risk LOH (and the nonappearance of any other high-risk LOH) in the site of the OPL at the histological sample after immunotherapy treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety of immunotherapy in the treatment of OPL</measure>
    <time_frame>Through study completion, an average of 5 years</time_frame>
    <description>Grade 3-5 adverse events or any treatment interruption due to toxicities (safety)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Grading of OPL</measure>
    <time_frame>6 months</time_frame>
    <description>Change of histological grading of OPL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Multi-omic signatures</measure>
    <time_frame>6 months and through study completion, an average of 5 years</time_frame>
    <description>Identification of multi-omic signatures associated with response to immunotherapy</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">240</enrollment>
  <condition>Oral Premalignant Lesions</condition>
  <arm_group>
    <arm_group_label>Single Arm Avelumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Avelumab monotherapy on the Day 1 (± 2 days) of a 2-week treatment cycle for 4 administrations.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Avelumab</intervention_name>
    <description>Subjects will receive treatment with avelumab monotherapy 800 mg as a 60-minute IV infusion on the Day 1 (± 2 days) of a 2-week treatment cycle for 4 administrations.</description>
    <arm_group_label>Single Arm Avelumab</arm_group_label>
    <other_name>Bavencio</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed written informed consent;&#xD;
&#xD;
          2. Male or female &gt; 18 years of age;&#xD;
&#xD;
          3. ECOG Performance status (PS) 0-1;&#xD;
&#xD;
          4. Clinical and histological evidence of OPL with high risk of malignant transformation&#xD;
             as defined by LOH at 3p14 and/or 9p21 plus at least at one additional chromosomal site&#xD;
             (4q, 8p,11p,13q, or 17p) or patients with a prior oral cancer history and LOH at 3p14&#xD;
             and/or 9p21 (LOH defined according to EPOC trial). These conditions define &quot;LOH&#xD;
             positivity&quot;;&#xD;
&#xD;
          5. OPL with a histological definition of dysplasia and a minimum diameter of at least 20&#xD;
             mm;&#xD;
&#xD;
          6. Be willing to provide tissue from newly obtained oral biopsies;&#xD;
&#xD;
          7. Not receiving chronic systemic steroidal therapy or any immunosuppressive therapy&#xD;
             within 7 days prior to the first treatment; absence of active autoimmune disease that&#xD;
             required systemic treatment in the past 2 years, except the following:&#xD;
&#xD;
               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g.&#xD;
                  intra-articular injection);&#xD;
&#xD;
               -  Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or&#xD;
                  equivalent;&#xD;
&#xD;
               -  Steroids as premedication for hypersensitivity reactions (e.g. CT scan&#xD;
                  premedication);&#xD;
&#xD;
          8. Adequate bone marrow function: neutrophils &gt; 1.5 x 109/L, platelets &gt; 100 x 109/L,&#xD;
             haemoglobin &gt; 9 g/dL;&#xD;
&#xD;
          9. Adequate liver function: bilirubin &lt; 2 X upper normal limit (except known medical&#xD;
             reason not interfering with liver function, such as Gilbert disease), SGOT, SGPT, AP,&#xD;
             GGT &lt; 3 x ULN;&#xD;
&#xD;
         10. Adequate renal function: calculated or analysed creatinine clearance &gt; 60 mL/min;&#xD;
&#xD;
         11. If of childbearing potential, willingness to use effective contraceptive method (Pearl&#xD;
             Index &lt; 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant,&#xD;
             transdermal patch, a combination of two barrier methods (condom and diaphragm),&#xD;
             sterilization, sexual abstinence for the study duration and 2 months post-dosing.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous immunotherapy (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody or any&#xD;
             other antibody or drug specifically targeting T-cell co-stimulation or immune&#xD;
             checkpoint receptors);&#xD;
&#xD;
          2. Oral lesions due to lichen planus;&#xD;
&#xD;
          3. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive&#xD;
             therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency&#xD;
             syndrome (AIDS)-related illness;&#xD;
&#xD;
          4. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or&#xD;
             chronic infection;&#xD;
&#xD;
          5. Vaccination within 4 weeks of the first dose of avelumab and while on trial is&#xD;
             prohibited except for the administration of inactivated vaccines (for example,&#xD;
             inactivated influenza vaccines);&#xD;
&#xD;
          6. Clinically significant cardiovascular disease, e.g. cardiac failure of New York Heart&#xD;
             Association classes III-IV, uncontrolled coronary artery disease, cardiomyopathy,&#xD;
             uncontrolled arrhythmia, uncontrolled hypertension, or history of myocardial&#xD;
             infarction in the last 12 months;&#xD;
&#xD;
          7. Significant neurologic or psychiatric disorders including dementia or seizures;&#xD;
&#xD;
          8. Active uncontrolled infection (requiring IV antibiotics) or active tuberculosis;&#xD;
&#xD;
          9. Active disseminated intravascular coagulation;&#xD;
&#xD;
         10. Other serious underlying medical conditions which could impair the ability of the&#xD;
             patient to participate into the study;&#xD;
&#xD;
         11. Having participated in another clinical trial or having received any investigational&#xD;
             agent in the preceding 30 days before study entry;&#xD;
&#xD;
         12. Known allergic/hypersensitivity reaction to any of the components of the treatment;&#xD;
&#xD;
         13. Pregnancy (absence confirmed by serum/urine beta HCG) or breastfeeding;&#xD;
&#xD;
         14. Other active malignancy within 3 years, with the exception of a history of a previous,&#xD;
             adequately treated:&#xD;
&#xD;
               -  basal cell carcinoma of the skin&#xD;
&#xD;
               -  pre-invasive carcinoma of the cervix&#xD;
&#xD;
               -  superficial bladder cancer&#xD;
&#xD;
               -  carcinoma in situ of the prostate, cervix or breast,&#xD;
&#xD;
               -  head and neck squamous cell carcinoma, surgically treated (radiotherapy treatment&#xD;
                  not allowed);&#xD;
&#xD;
         15. Legal incapacity or limited legal capacity;&#xD;
&#xD;
         16. Medical, psychological or socio-geographical condition or situation which in the&#xD;
             opinion of the investigator would not permit the patient to complete the study or sign&#xD;
             meaningful informed consent;&#xD;
&#xD;
         17. Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes&#xD;
             mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone&#xD;
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to&#xD;
             recur in the absence of an external trigger are permitted to be enrolled;&#xD;
&#xD;
         18. Conditions requiring systemic treatment with either corticosteroids (&gt; 10 mg daily&#xD;
             prednisone equivalents) or other immunosuppressive medications within 7 days of study&#xD;
             drug administration. Inhaled or topical steroids, steroids as premedication for&#xD;
             hypersensitivity reactions and adrenal replacement doses &gt; 10 mg daily prednisone&#xD;
             equivalents are permitted in the absence of active autoimmune disease.&#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_contact>
    <last_name>Paolo Bossi</last_name>
    <phone>+390303996536</phone>
    <email>paolo.bossi@unibs.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mariarita Arenella</last_name>
    <phone>+39 089 301545</phone>
    <email>mariarita.arenella@cr-technology.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Istituto di Candiolo - Fondazione del Piemonte per l'Oncologia - IRCCS</name>
      <address>
        <city>Candiolo</city>
        <state>Torino</state>
        <zip>10060</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Giovanni Succo</last_name>
      <email>giovannisucco@hotmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>ASST Spedali Civili di Brescia</name>
      <address>
        <city>Brescia</city>
        <zip>25123</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paolo Bossi</last_name>
      <phone>+390303996536</phone>
      <email>paolo.bossi@unibs.it</email>
    </contact>
    <contact_backup>
      <last_name>Cristina Gurizzan</last_name>
      <phone>+390303996536</phone>
      <email>gurizzancristina@gmail.com</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>IRCSS Ospedale Policlinico San Martino</name>
      <address>
        <city>Genova</city>
        <zip>16132</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Giorgio Peretti</last_name>
      <email>giorgioperetti18@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Istituto europeo di oncologia</name>
      <address>
        <city>Milano</city>
        <zip>20141</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Mohssen Ansarin</last_name>
      <email>mohssen.ansarin@ieo.it</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Istituto nazionale dei tumori Regina Elena</name>
      <address>
        <city>Roma</city>
        <zip>00144</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Raul Pellini</last_name>
      <email>raul.pellini@ifo.gov.it</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>August 3, 2020</study_first_submitted>
  <study_first_submitted_qc>August 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2020</study_first_posted>
  <last_update_submitted>November 27, 2020</last_update_submitted>
  <last_update_submitted_qc>November 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 1, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</investigator_affiliation>
    <investigator_full_name>Paolo Bossi</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Precancerous Conditions</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Avelumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>After the end of the trial, the genomic data of OPL will be made publicly available through GEO</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>12 months after the end of the trial, for at least 1 year</ipd_time_frame>
    <ipd_access_criteria>NS</ipd_access_criteria>
  </patient_data>
  <!-- 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/NCT04504552
org study id: IMPEDE
nct id: NCT04504552
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This trial is designed as a prospective, multi-centre, open-label, single-arm, phase II
      study.

      Oral Premalignant Lesions (OPL) may be considered the equilibrium phase of the immunoediting
      concept, i.e. a dynamic process between the tumour cells and the immune system including
      surveillance by the immune system or tumour progression. Thus, an imbalance in
      immunosuppressive microenvironment is a possible key in malignant transformation. In this
      regard, the activation of the PD-1/PD-L1 pathway has a central role, witnessed by the
      expression of PD-L1 by multiple cell types within the microenvironment of OPL
      (tumour-associated macrophages, fibroblasts, lymphocytes) and by the fact that PD-L1
      expression in epithelial and subepithelial cells is associated with malignant transformation.
      The use of checkpoint inhibitors in this setting seems to be justified by this rationale.
      Employing intermediate end-point markers during preventive strategies against OPL may allow
      the conduction of smaller trials, able to give insights for designing larger studies and to
      better select the population receiving benefit from the treatment. In this regard, the
      evaluation of phenotypic changes (reduction in size or in grade of dysplasia) may not be
      enough to assess the potential benefit of an intervention. Modulation of molecular markers
      may be more precise indicator of oral cancer risk in patients with OPL. Thus, the change in
      LOH at critical loci may be considered intermediate end-point biomarkers of prevention as
      well as predictors of cancer risk at baseline. Previous experience with anti-EGFR agents
      showed the feasibility of such measures in a prevention trial.
OPL represent the most common oral precancerous condition, with a potential of malignant
      transformation varying from 1% to 47% in different studies. Among molecular markers, the most
      effective in predicting oral cancer risk is loss of heterozygosity (LOH), which may appear in
      tissues with different histological grade of dysplasia. Patients carrying OPL with LOH at
      3p14 and/or 9p21 plus LOH at another locus have an expected 3-year risk of developing oral
      cancer of 35%. This chromosomal profile is found in about 28% of OPL. Moreover, when a
      patient has previously suffered from oral cavity cancer, the 3-year risk of malignant
      transformation for OPL with such a chromosomal profile reaches 69%. The presence of tumour
      suppressor genes (TSGs) at these chromosomal loci explains the potential for cancer
      development in the presence of such alterations.

      The clinical management of small OPL is excision by a cold knife or laser. However, treatment
      is not effective to prevent oral cancer in patients. Lesions recur frequently and transform
      subsequently, and tumours develop in the same or adjacent anatomical region. For larger OPL
      the clinical management is limited to lifelong surveillance. To improve clinical management
      of OPLs, the arsenal of treatments should be expanded.

      Therefore, this study is aimed at treating high-risk OPL with a short course of immunotherapy
      (avelumab)
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recurrence-free survival or malignant transformation-free survival
time frame: Every 2 weeks for the first 6 months, then every month for 1 year, then every 3 months for 30 months
description: Recurrence or malignancy-free survival since immunotherapy start, for which the events of interest are the recurrence of OPL with LOH or malignant transformation of OPL
measure: Change in LOH status (positive to negative) of OPL
time frame: 6 months
description: Change in LOH status (positive to negative) of OPL after 6 months since the start of immunotherapy. This is defined as disappearance of any high-risk LOH (and the nonappearance of any other high-risk LOH) in the site of the OPL at the histological sample after immunotherapy treatment
measure: Safety of immunotherapy in the treatment of OPL
time frame: Through study completion, an average of 5 years
description: Grade 3-5 adverse events or any treatment interruption due to toxicities (safety)
measure: Grading of OPL
time frame: 6 months
description: Change of histological grading of OPL
measure: Multi-omic signatures
time frame: 6 months and through study completion, an average of 5 years
description: Identification of multi-omic signatures associated with response to immunotherapy
arm group label: Single Arm Avelumab
arm group type: Experimental
description: Avelumab monotherapy on the Day 1 (± 2 days) of a 2-week treatment cycle for 4 administrations.
intervention type: Drug
intervention name: Avelumab
description: Subjects will receive treatment with avelumab monotherapy 800 mg as a 60-minute IV infusion on the Day 1 (± 2 days) of a 2-week treatment cycle for 4 administrations.
arm group label: Single Arm Avelumab
other name: Bavencio
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Paolo Bossi
phone: +390303996536
email: paolo.bossi@unibs.it
last name: Mariarita Arenella
phone: +39 089 301545
email: mariarita.arenella@cr-technology.com
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
investigator full name: Paolo Bossi
investigator title: Professor
mesh term: Precancerous Conditions
mesh term: Avelumab
sharing ipd: Yes
ipd description: After the end of the trial, the genomic data of OPL will be made publicly available through GEO
ipd info type: Clinical Study Report (CSR)
ipd time frame: 12 months after the end of the trial, for at least 1 year
ipd access criteria: NS