<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/NCT03830229</url>
  </required_header>
  <id_info>
    <org_study_id>190049</org_study_id>
    <secondary_id>19-C-0049</secondary_id>
    <nct_id>NCT03830229</nct_id>
  </id_info>
  <brief_title>Long Term Follow-up of Mesothelioma Patients and Their Family Members With Germline Mutations in BAP1 and Other Genes</brief_title>
  <official_title>Long Term Follow-up of Mesothelioma Patients and Their Family Members With Germline Mutations in BAP1 and Other Genes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      -A gene provides instructions to the body. Mutated genes can sometimes cause cancer. Germline&#xD;
      mutations are those people are born with. These mutations in the BAP1 gene can cause&#xD;
      mesothelioma and other cancers. Researchers want to study people with germline mutations of&#xD;
      BAP1 and other genes known to cause cancer.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      -To learn how cancer might develop in people with certain gene mutations.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      -People ages 2 and older with a germline mutation in BAP1 or another gene that might cause&#xD;
      cancer&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with:&#xD;
&#xD;
             -  Medical and family history&#xD;
&#xD;
             -  Saliva test&#xD;
&#xD;
        -  Participants with mesothelioma will be in the NIH Group. Participants without&#xD;
           mesothelioma can choose to be in either the NIH Group or the Remote Group.&#xD;
&#xD;
        -  Remote Group participants will have a medical and family history by phone. If they have&#xD;
           tumor tissue from a previous surgery, it will be tested. They will be contacted once a&#xD;
           year by phone.&#xD;
&#xD;
        -  NIH Group participants will have a baseline visit. This can take up to 4 days. They may&#xD;
           have to stay in the area overnight. The visit will include:&#xD;
&#xD;
             -  Physical exam&#xD;
&#xD;
             -  Evaluation of tumor tissue if available&#xD;
&#xD;
             -  Optional tumor biopsy&#xD;
&#xD;
             -  Blood tests&#xD;
&#xD;
             -  Scans: A machine will take pictures of the body.&#xD;
&#xD;
             -  Photographs of skin lesions or other issues&#xD;
&#xD;
             -  Skin exam&#xD;
&#xD;
             -  Eye exam&#xD;
&#xD;
        -  NIH Group participants will have visits once or twice a year. These will include a&#xD;
           physical exam, lab tests, scans, and other tests as needed.&#xD;
&#xD;
        -  Participants who have a confirmed mutation will be asked to contact any relatives who&#xD;
           may be at risk and ask them about joining the study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  BRCA1-Associated Protein-1 (BAP1), a deubiquitinase involved in regulating DNA repair&#xD;
           enzymes, is believed to be a prominent mutation in malignant mesothelioma&#xD;
&#xD;
        -  Germline mutations involving BAP1 have been reported in familial studies. These have&#xD;
           been associated with a higher likelihood of mesothelioma as well as several other&#xD;
           malignancies, including uveal melanoma, cutaneous melanomas, renal cell carcinoma and&#xD;
           cholangiocarcinoma&#xD;
&#xD;
        -  BAP1 mutations, if found, have a high probability of detecting multiple malignancies in&#xD;
           family members.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      -To characterize the natural and clinical history of malignant mesothelioma patients and&#xD;
      their family members who have germline mutations in BAP1 and other DNA repair/cancer&#xD;
      predisposition genes&#xD;
&#xD;
      Eligibility for Genetic Testing:&#xD;
&#xD;
      Cohort 1&#xD;
&#xD;
      -Individual with mesothelioma with deleterious germline mutations in BAP1 or another&#xD;
      DNA-repair/cancer predisposition gene(s) (previous testing may have been research or&#xD;
      clinical)&#xD;
&#xD;
      OR&#xD;
&#xD;
        -  Individual with a diagnosis of mesothelioma who is otherwise eligible for testing on&#xD;
           Cohort 2&#xD;
&#xD;
        -  Age greater than or equal to 2&#xD;
&#xD;
      Cohort 2&#xD;
&#xD;
      -Individual with a germline BAP1 mutation who does not have a history of mesothelioma&#xD;
      (previous testing may have been research or clinical)&#xD;
&#xD;
      OR&#xD;
&#xD;
      -Individual with no personal history of mesothelioma with:&#xD;
&#xD;
      --a first degree biological relative (living or deceased) with a history of mesothelioma&#xD;
&#xD;
      OR&#xD;
&#xD;
      --a first degree biological relative with a CLIA confirmed germline mutation in BAP1&#xD;
&#xD;
      OR&#xD;
&#xD;
      --a second degree biological relative with a CLIA confirmed germline mutation in BAP1 if&#xD;
      relevant first degree relative is deceased or unavailable for testing&#xD;
&#xD;
      OR&#xD;
&#xD;
      --a first degree biological relative with mesothelioma and a CLIA confirmed germline mutation&#xD;
      in another DNA-repair/cancer predisposition genes&#xD;
&#xD;
      OR&#xD;
&#xD;
      --a second degree biological relative with mesothelioma and a CLIA confirmed germline&#xD;
      mutation in BAP1&#xD;
&#xD;
      -Age greater than or equal to 16 unless participant has a BAP1 mutation or a first degree&#xD;
      biological relative with a confirmed TP53 or BAP1 germline mutation; in such cases, will&#xD;
      begin screening at age greater than or equal to 2&#xD;
&#xD;
      Eligibility for Surveillance:&#xD;
&#xD;
      Cohort 1&#xD;
&#xD;
      -No additional criteria&#xD;
&#xD;
      Cohort 2&#xD;
&#xD;
      -Testing performed on study must confirm presence of germline mutation in BAP1 or another DNA&#xD;
      repair/cancer predisposition gene(s)&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Individuals with suspected hereditary predisposition to mesothelioma and their families&#xD;
           will be recruited to assess for genetic mutations, and to study the natural history of&#xD;
           malignancies occurring in germline BAP1 mutations as well as other mutations involved in&#xD;
           DNA repair.&#xD;
&#xD;
        -  Screening examinations will be offered to those with germline BAP1 mutations as well as&#xD;
           other mutations involved in DNA repair/cancer predisposition.&#xD;
&#xD;
        -  We will determine if there is a relationship between germline mutation and disease&#xD;
           phenotype.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 13, 2019</start_date>
  <completion_date type="Anticipated">July 5, 2027</completion_date>
  <primary_completion_date type="Anticipated">July 6, 2026</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence and frequencies of Cancers</measure>
    <time_frame>ongoing</time_frame>
    <description>Standard exploratory and descriptive measures will be used. Counts, incidence, and frequencies of cancers identified via screening procedures on this trial will be reported, all in the context of an exploratory study with appropriate caveats.</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">1000</enrollment>
  <condition>Mesothelioma</condition>
  <condition>Families</condition>
  <arm_group>
    <arm_group_label>1/Germline positive mesothelioma</arm_group_label>
    <description>Individuals with mesothelioma who have a BAP1 or other DNA repair/cancer predisposition mutation regardless of CLIA confirmation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2/CLIA confirmed germline mutation without mesothelioma</arm_group_label>
    <description>Individuals with a CLIA confirmed BAP1 or other DNA repair/cancer predisposition mutation who do not have a diagnosis of mesothelioma</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Persons with mesothelioma and family members as well as individuals with CLIA documented&#xD;
        germline BAP-1 and other DNA repair/cancer predisposition mutations&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        -  Inclusion Criteria:&#xD;
&#xD;
        Inclusion Criteria for Genetic Testing:&#xD;
&#xD;
        Cohort 1:&#xD;
&#xD;
          -  Subject with pathology confirming a diagnosis of mesothelioma.&#xD;
&#xD;
          -  Subject must have a deleterious germline BAP1 mutation. Results from either research&#xD;
             or clinical analyses are sufficient for this criterion.&#xD;
&#xD;
        OR&#xD;
&#xD;
        -Subject with mesothelioma otherwise eligible for genetic testing in Cohort 2&#xD;
&#xD;
        OR&#xD;
&#xD;
          -  Subject must have deleterious germline mutation in another DNA repair/cancer&#xD;
             predisposition gene(s) that is listed on a commercially available, cancer-associated&#xD;
             common or customized gene panel. Results from either research or clinical analyses are&#xD;
             sufficient for this criterion.&#xD;
&#xD;
          -  Age greater than or equal to 2 years&#xD;
&#xD;
        Cohort 2:&#xD;
&#xD;
        -Individual with a germline BAP1 mutation who does not have a history of mesothelioma&#xD;
        (other cancers are allowed). Results from either research or clinical analyses are&#xD;
        sufficient for this criterion.&#xD;
&#xD;
        OR&#xD;
&#xD;
        -Individual with no history of mesothelioma with:&#xD;
&#xD;
        --A biological first degree relative (living or deceased) with a history of mesothelioma&#xD;
&#xD;
        OR&#xD;
&#xD;
        --A first degree biological relative with a CLIA confirmed germline mutation in BAP1&#xD;
&#xD;
        OR&#xD;
&#xD;
        --A second degree biological relative with a CLIA confirmed germline mutation in BAP1 if&#xD;
        relevant first degree relative is deceased or unavailable for testing,&#xD;
&#xD;
        OR&#xD;
&#xD;
        --A first degree biological relative with mesothelioma and a CLIA confirmed germline&#xD;
        mutation in another DNA-repair/cancer predisposition gene that is listed on a commercially&#xD;
        available, cancer-associated common or customized gene panel&#xD;
&#xD;
        OR&#xD;
&#xD;
          -  A second degree biological relative with mesothelioma and a CLIA confirmed germline&#xD;
             mutation in BAP1&#xD;
&#xD;
             -Age:&#xD;
&#xD;
          -  greater than or equal to 2 years for subjects with a BAP1 or TP53 mutation or with a&#xD;
             first degree relative relative that has a germline mutation in TP53 or BAP1&#xD;
&#xD;
          -  greater than or equal to 16 years for all other eligible potential mutations&#xD;
&#xD;
        All participants must understand and be willing to sign a written informed consent&#xD;
&#xD;
        Exclusion Criteria for Genetic Testing&#xD;
&#xD;
        None&#xD;
&#xD;
        Inclusion Criteria for Surveillance:&#xD;
&#xD;
          -  Genetic testing criteria including age restrictions for respective cohorts must be met&#xD;
&#xD;
          -  Subjects in Cohort 1 may be enrolled with positive results for germline BAP1 mutation&#xD;
             or another DNA repair/cancer predisposition gene(s) that is listed on a commercially&#xD;
             available, cancer-associated common or customized gene panel regardless of CLIA&#xD;
             confirmation&#xD;
&#xD;
          -  Subjects in Cohort 2 must have CLIA confirmed germline BAP1 mutation or another DNA&#xD;
             repair/cancer predisposition gene(s) that is listed on a commercially available,&#xD;
             cancer-associated common or customized gene panel&#xD;
&#xD;
        Exclusion Criteria for Surveillance:&#xD;
&#xD;
        None&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Raffit Hassan, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maria G Agra, R.N.</last_name>
    <phone>(240) 858-3152</phone>
    <email>mariagracia.agra@nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Raffit Hassan, M.D.</last_name>
    <phone>(240) 760-6232</phone>
    <email>rh276q@nih.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>For more information at the NIH Clinical Center contact National Cancer Institute Referral Office</last_name>
      <phone>888-624-1937</phone>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2019-C-0049.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>August 2, 2023</verification_date>
  <study_first_submitted>February 2, 2019</study_first_submitted>
  <study_first_submitted_qc>February 2, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 5, 2019</study_first_posted>
  <last_update_submitted>August 3, 2023</last_update_submitted>
  <last_update_submitted_qc>August 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>DNA Repair Genes</keyword>
  <keyword>Natural History</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mesothelioma</mesh_term>
    <mesh_term>Mesothelioma, Malignant</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition all large scale genomic sequencing data will be shared with subscribers to dbGaP.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Clinical data in BTRIS will be shared throughout the course of the study and indefinitely with the permission of the investigator.@@@@@@Genomic data will be shared from the time of upload to dbGaP.</ipd_time_frame>
    <ipd_access_criteria>Clinical IPD will be shared through the BTRIS database for open ended analysis. All BTRIS subscribers, generally limited to the NIH Clinical Center, may request data.@@@@@@Genomic IPD will be shared through dbGaP, per rules of the database, for purposes of genomic analysis.</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/NCT03830229
org study id: 190049
secondary id: 19-C-0049
nct id: NCT03830229
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Background:

      -A gene provides instructions to the body. Mutated genes can sometimes cause cancer. Germline
      mutations are those people are born with. These mutations in the BAP1 gene can cause
      mesothelioma and other cancers. Researchers want to study people with germline mutations of
      BAP1 and other genes known to cause cancer.

      Objective:

      -To learn how cancer might develop in people with certain gene mutations.

      Eligibility:

      -People ages 2 and older with a germline mutation in BAP1 or another gene that might cause
      cancer

      Design:

        -  Participants will be screened with:

             -  Medical and family history

             -  Saliva test

        -  Participants with mesothelioma will be in the NIH Group. Participants without
           mesothelioma can choose to be in either the NIH Group or the Remote Group.

        -  Remote Group participants will have a medical and family history by phone. If they have
           tumor tissue from a previous surgery, it will be tested. They will be contacted once a
           year by phone.

        -  NIH Group participants will have a baseline visit. This can take up to 4 days. They may
           have to stay in the area overnight. The visit will include:

             -  Physical exam

             -  Evaluation of tumor tissue if available

             -  Optional tumor biopsy

             -  Blood tests

             -  Scans: A machine will take pictures of the body.

             -  Photographs of skin lesions or other issues

             -  Skin exam

             -  Eye exam

        -  NIH Group participants will have visits once or twice a year. These will include a
           physical exam, lab tests, scans, and other tests as needed.

        -  Participants who have a confirmed mutation will be asked to contact any relatives who
           may be at risk and ask them about joining the study.
Background:

        -  BRCA1-Associated Protein-1 (BAP1), a deubiquitinase involved in regulating DNA repair
           enzymes, is believed to be a prominent mutation in malignant mesothelioma

        -  Germline mutations involving BAP1 have been reported in familial studies. These have
           been associated with a higher likelihood of mesothelioma as well as several other
           malignancies, including uveal melanoma, cutaneous melanomas, renal cell carcinoma and
           cholangiocarcinoma

        -  BAP1 mutations, if found, have a high probability of detecting multiple malignancies in
           family members.

      Objectives:

      -To characterize the natural and clinical history of malignant mesothelioma patients and
      their family members who have germline mutations in BAP1 and other DNA repair/cancer
      predisposition genes

      Eligibility for Genetic Testing:

      Cohort 1

      -Individual with mesothelioma with deleterious germline mutations in BAP1 or another
      DNA-repair/cancer predisposition gene(s) (previous testing may have been research or
      clinical)

      OR

        -  Individual with a diagnosis of mesothelioma who is otherwise eligible for testing on
           Cohort 2

        -  Age greater than or equal to 2

      Cohort 2

      -Individual with a germline BAP1 mutation who does not have a history of mesothelioma
      (previous testing may have been research or clinical)

      OR

      -Individual with no personal history of mesothelioma with:

      --a first degree biological relative (living or deceased) with a history of mesothelioma

      OR

      --a first degree biological relative with a CLIA confirmed germline mutation in BAP1

      OR

      --a second degree biological relative with a CLIA confirmed germline mutation in BAP1 if
      relevant first degree relative is deceased or unavailable for testing

      OR

      --a first degree biological relative with mesothelioma and a CLIA confirmed germline mutation
      in another DNA-repair/cancer predisposition genes

      OR

      --a second degree biological relative with mesothelioma and a CLIA confirmed germline
      mutation in BAP1

      -Age greater than or equal to 16 unless participant has a BAP1 mutation or a first degree
      biological relative with a confirmed TP53 or BAP1 germline mutation; in such cases, will
      begin screening at age greater than or equal to 2

      Eligibility for Surveillance:

      Cohort 1

      -No additional criteria

      Cohort 2

      -Testing performed on study must confirm presence of germline mutation in BAP1 or another DNA
      repair/cancer predisposition gene(s)

      Design:

        -  Individuals with suspected hereditary predisposition to mesothelioma and their families
           will be recruited to assess for genetic mutations, and to study the natural history of
           malignancies occurring in germline BAP1 mutations as well as other mutations involved in
           DNA repair.

        -  Screening examinations will be offered to those with germline BAP1 mutations as well as
           other mutations involved in DNA repair/cancer predisposition.

        -  We will determine if there is a relationship between germline mutation and disease
           phenotype.
observational model: Cohort
time perspective: Prospective
measure: Incidence and frequencies of Cancers
time frame: ongoing
description: Standard exploratory and descriptive measures will be used. Counts, incidence, and frequencies of cancers identified via screening procedures on this trial will be reported, all in the context of an exploratory study with appropriate caveats.
arm group label: 1/Germline positive mesothelioma
description: Individuals with mesothelioma who have a BAP1 or other DNA repair/cancer predisposition mutation regardless of CLIA confirmation
arm group label: 2/CLIA confirmed germline mutation without mesothelioma
description: Individuals with a CLIA confirmed BAP1 or other DNA repair/cancer predisposition mutation who do not have a diagnosis of mesothelioma
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 2 Years
maximum age: N/A
healthy volunteers: No
last name: Raffit Hassan, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
last name: Maria G Agra, R.N.
phone: (240) 858-3152
email: mariagracia.agra@nih.gov
last name: Raffit Hassan, M.D.
phone: (240) 760-6232
email: rh276q@nih.gov
facility: 
status: Recruiting
contact: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2019-C-0049.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Mesothelioma
mesh term: Mesothelioma, Malignant
sharing ipd: Yes
ipd description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition all large scale genomic sequencing data will be shared with subscribers to dbGaP.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data in BTRIS will be shared throughout the course of the study and indefinitely with the permission of the investigator.@@@@@@Genomic data will be shared from the time of upload to dbGaP.
ipd access criteria: Clinical IPD will be shared through the BTRIS database for open ended analysis. All BTRIS subscribers, generally limited to the NIH Clinical Center, may request data.@@@@@@Genomic IPD will be shared through dbGaP, per rules of the database, for purposes of genomic analysis.