<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/NCT04452292</url>
  </required_header>
  <id_info>
    <org_study_id>MCC-20-GI-112-PMC; MULTI-37</org_study_id>
    <secondary_id>KL2TR001996</secondary_id>
    <secondary_id>UL1TR001998</secondary_id>
    <nct_id>NCT04452292</nct_id>
  </id_info>
  <brief_title>Next Generation Sequencing-Based Stratification of Front Line Treatment of HighGrade Neuroendocrine Carcinoma</brief_title>
  <acronym>PRECISION-NEC</acronym>
  <official_title>A Pilot Feasibility Study of Next Generation Sequencing-Based Stratification of Front Line Treatment of HighGrade Neuroendocrine Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Charles Kunos</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Center for Advancing Translational Sciences (NCATS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Kentucky</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      PRECISION-NEC is a single-center, open-label, pilot feasibility study of molecularly defined&#xD;
      subtypes of metastatic high-grade neuroendocrine carcinoma (HG-NEC). The hypothesis is that&#xD;
      HG-NEC (excluding small cell carcinoma) can be segregated based on mutational analysis and&#xD;
      that next generation sequencing (NGS)-based assignment of therapy is feasible and will&#xD;
      potentially improve the outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Neuroendocrine tumors vary widely in both disease site and grade, ranging from low grade,&#xD;
      relatively benign carcinoid tumors to aggressive and rapidly fatal high-grade neuroendocrine&#xD;
      carcinomas. High-grade neuroendocrine carcinomas (HG-NECs) can originate anywhere in the&#xD;
      body, and are highly aggressive, with dismal 5-year overall survival rates. The lung and&#xD;
      gastrointestinal tract (small bowel, colon, rectum, or pancreas) form the majority of these&#xD;
      HG-NECs sites. HG-NECs are classified into three subtypes based on histopathology,&#xD;
      specifically, as small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma&#xD;
      (LCNEC), or poorly differentiated neuroendocrine carcinoma.&#xD;
&#xD;
      There is a lack of consensus for upfront systemic regimens for HG-NECs and as such, treatment&#xD;
      is often per physician preference. Most often, HG-NECs are treated with platinum-based&#xD;
      chemotherapeutic regimens, with marked heterogeneity in response. It is well established that&#xD;
      small cell neuroendocrine carcinomas are characterized by a co-mutation for TP53 and RB1, and&#xD;
      are exceptionally platinum-sensitive. However less is known about LCNECs.&#xD;
&#xD;
      LCNEC was first introduced in 1991 by Travis et. al as a new type of lung cancer. The 2015&#xD;
      World Health Organization Classification categorized LCNEC under neuroendocrine tumors, along&#xD;
      with typical carcinoma, atypical carcinoma and the more undifferentiated tumor represented by&#xD;
      small cell lung cancer. Prior to 2015, LCNEC was classified under a general category of large&#xD;
      cell carcinoma, however as pathologists studied this entity in detail, it was evident that&#xD;
      LCNEC has a distinct clinicopathological identity. Histopathologically, these tumors are&#xD;
      characterized by high mitotic rate (more than 10 mitosis per high power field), extensive&#xD;
      necrosis, and neuroendocrine features, specifically the presence of chromogranin A, neuron&#xD;
      specific enolase and synaptophysin.&#xD;
&#xD;
      LCNEC is a rare and aggressive disease with a paucity of data regarding disease progression.&#xD;
      Precise incidence and prevalence is unknown. From 2003-2012, the Dutch Cancer Registry&#xD;
      reported 952 histologically confirmed new cases of pulmonary LCNECs. Among these cases, 383&#xD;
      patients presented with advanced disease, primarily metastases to liver, bone, or brain. The&#xD;
      prognosis is poor with overall 5-year survival for metastatic disease less than 5%, which is&#xD;
      similar to small cell lung cancer (SCLC), although some studies suggest that the prognosis&#xD;
      for early-stage LCNEC might be slightly better and similar to non-small cell lung cancer&#xD;
      (NSCLC).&#xD;
&#xD;
      Molecular profiling of small-cell neuroendocrine carcinomas is well established and&#xD;
      validated, indicating universally expressed co-mutation for TP53 and RB1. Recently there have&#xD;
      been attempts to define genomic profiles of LCNEC. The development of a 241-gene panel on&#xD;
      pulmonary tumors, next-generation sequencing allows LCNECs to be further defined.&#xD;
&#xD;
      Based on specific genetic signatures, Rekhtman and colleagues sub-classified 45 LCNECs into&#xD;
      two major cohorts: 1) small cell-like (TP53/RB1 co-mutated; n=18) and 2) non-small cell-like&#xD;
      (n=25), as well as one minor cohort (carcinoid-like n=2).&#xD;
&#xD;
      Similarly, molecular profiling of gastrointestinal high-grade neuroendocrine carcinomas&#xD;
      (GI-NECs) indicate that they can also be dichotomously categorized by the presence or absence&#xD;
      of co-mutations for TP53 and RB1.&#xD;
&#xD;
      Treatment regimens for small cell neuroendocrine carcinoma are well established, based on&#xD;
      clinical trials conducted in SCLC. In contrast, current guidelines regarding optimal&#xD;
      treatment for large-cell and poorly differentiated neuroendocrine carcinomas are nonexistent,&#xD;
      driven by the paucity of data on these rare and highly fatal tumors. Additionally, the World&#xD;
      Health Organization (WHO) recently defined a new subtype of high-grade neuroendocrine&#xD;
      carcinoma, mixed neuroendocrine neoplasm (MINEN), which features characteristics found in&#xD;
      large-cell carcinomas and in other tumor types, including adenocarcinomas for example.&#xD;
&#xD;
      To date, there are no prospective randomized clinical trials examining front line therapies&#xD;
      for metastatic HG-NECs, based on mutational profiles. This study will utilize recent genomic&#xD;
      profiles of high-grade large cell neuroendocrine carcinomas to guide and inform clinicians of&#xD;
      optimal treatments.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 14, 2021</start_date>
  <completion_date type="Actual">March 14, 2023</completion_date>
  <primary_completion_date type="Actual">May 4, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Sequencing Rate (Feasibility)</measure>
    <time_frame>2 months</time_frame>
    <description>Percentage of patients able to be sequenced within 2 months of the initial medical oncology visit.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Molecular Cohort Assignment (Feasibility)</measure>
    <time_frame>2 months</time_frame>
    <description>Percentage of patients who were successfully assigned into a molecularly-defined cohort (TP53/RB1 co-mutations or not).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-Free Survival (PFS)</measure>
    <time_frame>2 years</time_frame>
    <description>Duration of time from the first cycle of anticancer therapy to time of progressive disease or death from any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Response Rate</measure>
    <time_frame>2 years</time_frame>
    <description>Percentage of patients experiencing overall complete response (CR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Partial Response Rate</measure>
    <time_frame>2 years</time_frame>
    <description>Percentage of patients experiencing overall partial response (PR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progressive Disease Rate</measure>
    <time_frame>2 years</time_frame>
    <description>Percentage of patients experiencing overall progressive disease (PD).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stable Disease Rate</measure>
    <time_frame>2 years</time_frame>
    <description>Percentage of patients experiencing overall stable disease (SD).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Large-Cell Neuroendocrine Carcinoma</condition>
  <arm_group>
    <arm_group_label>No TP53/Rb1 Co-Mutation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TP53/Rb1 Co-Mutation Present</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma</intervention_name>
    <description>Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
    <arm_group_label>No TP53/Rb1 Co-Mutation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Treatment for Small Cell Lung Cancer</intervention_name>
    <description>Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
    <arm_group_label>TP53/Rb1 Co-Mutation Present</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed high grade neuroendocrine carcinoma that is metastatic and/or&#xD;
             not resectable&#xD;
&#xD;
          -  Adequate tissue available for genomic sequencing&#xD;
&#xD;
          -  ECOG status less than or equal to 2&#xD;
&#xD;
          -  Able to consent&#xD;
&#xD;
          -  Patient received up to two cycles of chemotherapy prior to enrollment&#xD;
&#xD;
          -  Adequate bone marrow function&#xD;
&#xD;
          -  Adequate hepatic function&#xD;
&#xD;
          -  Adequate renal function&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Small cell carcinoma&#xD;
&#xD;
          -  Psychiatric illness or social situations that limit compliance&#xD;
&#xD;
          -  Pregnant and nursing women&#xD;
&#xD;
          -  Patients who have completed more than two cycles of chemotherapy&#xD;
&#xD;
          -  Patients with resectable cancer or eligible for curative therapy&#xD;
&#xD;
          -  Patients with an actionable mutation for with guidelines recommend up-front therapy&#xD;
             with targeted agents&#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>Charles Kunos, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Kentucky</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Markey Cancer Center, University of Kentucky</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>June 24, 2020</study_first_submitted>
  <study_first_submitted_qc>June 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 30, 2020</study_first_posted>
  <results_first_submitted>April 21, 2023</results_first_submitted>
  <results_first_submitted_qc>April 21, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">May 17, 2023</results_first_posted>
  <last_update_submitted>April 21, 2023</last_update_submitted>
  <last_update_submitted_qc>April 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Kentucky</investigator_affiliation>
    <investigator_full_name>Charles Kunos</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>poorly differentiated neuroendocrine carcinoma</keyword>
  <keyword>NGS</keyword>
  <keyword>TP53/Rb1</keyword>
  <keyword>co-mutation</keyword>
  <keyword>molecular subtype</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Neuroendocrine</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 14, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/92/NCT04452292/Prot_SAP_ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Opened to accrual in 11/2020 was closed to enrollment on 11/2022 due to poor accrual. Target accrual was 15 participants.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>No TP53/Rb1 Co-Mutation</title>
          <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
        </group>
        <group group_id="P2">
          <title>TP53/Rb1 Co-Mutation Present</title>
          <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Closed to slow accrual and no participants were enrolled in TP53/Rb1 Co-Mutation Present arm</population>
      <group_list>
        <group group_id="B1">
          <title>No TP53/Rb1 Co-Mutation</title>
          <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
        </group>
        <group group_id="B2">
          <title>TP53/Rb1 Co-Mutation Present</title>
          <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
            <count group_id="B2" value="0"/>
            <count group_id="B3" value="2"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Sequencing Rate (Feasibility)</title>
        <description>Percentage of patients able to be sequenced within 2 months of the initial medical oncology visit.</description>
        <time_frame>2 months</time_frame>
        <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
        <group_list>
          <group group_id="O1">
            <title>No TP53/Rb1 Co-Mutation</title>
            <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
          </group>
          <group group_id="O2">
            <title>TP53/Rb1 Co-Mutation Present</title>
            <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
          </group>
        </group_list>
        <measure>
          <title>Sequencing Rate (Feasibility)</title>
          <description>Percentage of patients able to be sequenced within 2 months of the initial medical oncology visit.</description>
          <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Molecular Cohort Assignment (Feasibility)</title>
        <description>Percentage of patients who were successfully assigned into a molecularly-defined cohort (TP53/RB1 co-mutations or not).</description>
        <time_frame>2 months</time_frame>
        <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
        <group_list>
          <group group_id="O1">
            <title>No TP53/Rb1 Co-Mutation</title>
            <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
          </group>
          <group group_id="O2">
            <title>TP53/Rb1 Co-Mutation Present</title>
            <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
          </group>
        </group_list>
        <measure>
          <title>Molecular Cohort Assignment (Feasibility)</title>
          <description>Percentage of patients who were successfully assigned into a molecularly-defined cohort (TP53/RB1 co-mutations or not).</description>
          <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-Free Survival (PFS)</title>
        <description>Duration of time from the first cycle of anticancer therapy to time of progressive disease or death from any cause, whichever occurs first.</description>
        <time_frame>2 years</time_frame>
        <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
        <group_list>
          <group group_id="O1">
            <title>No TP53/Rb1 Co-Mutation</title>
            <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
          </group>
          <group group_id="O2">
            <title>TP53/Rb1 Co-Mutation Present</title>
            <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-Free Survival (PFS)</title>
          <description>Duration of time from the first cycle of anticancer therapy to time of progressive disease or death from any cause, whichever occurs first.</description>
          <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Complete Response Rate</title>
        <description>Percentage of patients experiencing overall complete response (CR).</description>
        <time_frame>2 years</time_frame>
        <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
        <group_list>
          <group group_id="O1">
            <title>No TP53/Rb1 Co-Mutation</title>
            <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
          </group>
          <group group_id="O2">
            <title>TP53/Rb1 Co-Mutation Present</title>
            <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
          </group>
        </group_list>
        <measure>
          <title>Complete Response Rate</title>
          <description>Percentage of patients experiencing overall complete response (CR).</description>
          <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Partial Response Rate</title>
        <description>Percentage of patients experiencing overall partial response (PR).</description>
        <time_frame>2 years</time_frame>
        <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
        <group_list>
          <group group_id="O1">
            <title>No TP53/Rb1 Co-Mutation</title>
            <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
          </group>
          <group group_id="O2">
            <title>TP53/Rb1 Co-Mutation Present</title>
            <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
          </group>
        </group_list>
        <measure>
          <title>Partial Response Rate</title>
          <description>Percentage of patients experiencing overall partial response (PR).</description>
          <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progressive Disease Rate</title>
        <description>Percentage of patients experiencing overall progressive disease (PD).</description>
        <time_frame>2 years</time_frame>
        <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
        <group_list>
          <group group_id="O1">
            <title>No TP53/Rb1 Co-Mutation</title>
            <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
          </group>
          <group group_id="O2">
            <title>TP53/Rb1 Co-Mutation Present</title>
            <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
          </group>
        </group_list>
        <measure>
          <title>Progressive Disease Rate</title>
          <description>Percentage of patients experiencing overall progressive disease (PD).</description>
          <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Stable Disease Rate</title>
        <description>Percentage of patients experiencing overall stable disease (SD).</description>
        <time_frame>2 years</time_frame>
        <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
        <group_list>
          <group group_id="O1">
            <title>No TP53/Rb1 Co-Mutation</title>
            <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
          </group>
          <group group_id="O2">
            <title>TP53/Rb1 Co-Mutation Present</title>
            <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
          </group>
        </group_list>
        <measure>
          <title>Stable Disease Rate</title>
          <description>Percentage of patients experiencing overall stable disease (SD).</description>
          <population>Two participants were enrolled in this study. Due to the possibility that participants could reasonably be identified due to low enrollment, data cannot be presented.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Only 2 participants were enrolled in this study. Based on the low enrolment number, no data is reported here in order to protect and maintain participant privacy/confidentiality.</time_frame>
      <desc>Only 2 participants were enrolled in this study. Based on the low enrolment number, no data is reported here in order to protect and maintain participant privacy/confidentiality.</desc>
      <group_list>
        <group group_id="E1">
          <title>No TP53/Rb1 Co-Mutation</title>
          <description>HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).&#xD;
Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.</description>
        </group>
        <group group_id="E2">
          <title>TP53/Rb1 Co-Mutation Present</title>
          <description>HG-LCNEC tumor with the TP53/Rb1 co-mutation.&#xD;
Treatment for Small Cell Lung Cancer: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Charles Kunos</name_or_title>
      <organization>University of Kentucky</organization>
      <phone>859-323-2354</phone>
      <email>charles.kunos@uky.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT04452292
org study id: MCC-20-GI-112-PMC; MULTI-37
secondary id: KL2TR001996
secondary id: UL1TR001998
nct id: NCT04452292
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
PRECISION-NEC is a single-center, open-label, pilot feasibility study of molecularly defined
      subtypes of metastatic high-grade neuroendocrine carcinoma (HG-NEC). The hypothesis is that
      HG-NEC (excluding small cell carcinoma) can be segregated based on mutational analysis and
      that next generation sequencing (NGS)-based assignment of therapy is feasible and will
      potentially improve the outcomes.
Neuroendocrine tumors vary widely in both disease site and grade, ranging from low grade,
      relatively benign carcinoid tumors to aggressive and rapidly fatal high-grade neuroendocrine
      carcinomas. High-grade neuroendocrine carcinomas (HG-NECs) can originate anywhere in the
      body, and are highly aggressive, with dismal 5-year overall survival rates. The lung and
      gastrointestinal tract (small bowel, colon, rectum, or pancreas) form the majority of these
      HG-NECs sites. HG-NECs are classified into three subtypes based on histopathology,
      specifically, as small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma
      (LCNEC), or poorly differentiated neuroendocrine carcinoma.

      There is a lack of consensus for upfront systemic regimens for HG-NECs and as such, treatment
      is often per physician preference. Most often, HG-NECs are treated with platinum-based
      chemotherapeutic regimens, with marked heterogeneity in response. It is well established that
      small cell neuroendocrine carcinomas are characterized by a co-mutation for TP53 and RB1, and
      are exceptionally platinum-sensitive. However less is known about LCNECs.

      LCNEC was first introduced in 1991 by Travis et. al as a new type of lung cancer. The 2015
      World Health Organization Classification categorized LCNEC under neuroendocrine tumors, along
      with typical carcinoma, atypical carcinoma and the more undifferentiated tumor represented by
      small cell lung cancer. Prior to 2015, LCNEC was classified under a general category of large
      cell carcinoma, however as pathologists studied this entity in detail, it was evident that
      LCNEC has a distinct clinicopathological identity. Histopathologically, these tumors are
      characterized by high mitotic rate (more than 10 mitosis per high power field), extensive
      necrosis, and neuroendocrine features, specifically the presence of chromogranin A, neuron
      specific enolase and synaptophysin.

      LCNEC is a rare and aggressive disease with a paucity of data regarding disease progression.
      Precise incidence and prevalence is unknown. From 2003-2012, the Dutch Cancer Registry
      reported 952 histologically confirmed new cases of pulmonary LCNECs. Among these cases, 383
      patients presented with advanced disease, primarily metastases to liver, bone, or brain. The
      prognosis is poor with overall 5-year survival for metastatic disease less than 5%, which is
      similar to small cell lung cancer (SCLC), although some studies suggest that the prognosis
      for early-stage LCNEC might be slightly better and similar to non-small cell lung cancer
      (NSCLC).

      Molecular profiling of small-cell neuroendocrine carcinomas is well established and
      validated, indicating universally expressed co-mutation for TP53 and RB1. Recently there have
      been attempts to define genomic profiles of LCNEC. The development of a 241-gene panel on
      pulmonary tumors, next-generation sequencing allows LCNECs to be further defined.

      Based on specific genetic signatures, Rekhtman and colleagues sub-classified 45 LCNECs into
      two major cohorts: 1) small cell-like (TP53/RB1 co-mutated; n=18) and 2) non-small cell-like
      (n=25), as well as one minor cohort (carcinoid-like n=2).

      Similarly, molecular profiling of gastrointestinal high-grade neuroendocrine carcinomas
      (GI-NECs) indicate that they can also be dichotomously categorized by the presence or absence
      of co-mutations for TP53 and RB1.

      Treatment regimens for small cell neuroendocrine carcinoma are well established, based on
      clinical trials conducted in SCLC. In contrast, current guidelines regarding optimal
      treatment for large-cell and poorly differentiated neuroendocrine carcinomas are nonexistent,
      driven by the paucity of data on these rare and highly fatal tumors. Additionally, the World
      Health Organization (WHO) recently defined a new subtype of high-grade neuroendocrine
      carcinoma, mixed neuroendocrine neoplasm (MINEN), which features characteristics found in
      large-cell carcinomas and in other tumor types, including adenocarcinomas for example.

      To date, there are no prospective randomized clinical trials examining front line therapies
      for metastatic HG-NECs, based on mutational profiles. This study will utilize recent genomic
      profiles of high-grade large cell neuroendocrine carcinomas to guide and inform clinicians of
      optimal treatments.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Sequencing Rate (Feasibility)
time frame: 2 months
description: Percentage of patients able to be sequenced within 2 months of the initial medical oncology visit.
measure: Molecular Cohort Assignment (Feasibility)
time frame: 2 months
description: Percentage of patients who were successfully assigned into a molecularly-defined cohort (TP53/RB1 co-mutations or not).
measure: Progression-Free Survival (PFS)
time frame: 2 years
description: Duration of time from the first cycle of anticancer therapy to time of progressive disease or death from any cause, whichever occurs first.
measure: Complete Response Rate
time frame: 2 years
description: Percentage of patients experiencing overall complete response (CR).
measure: Partial Response Rate
time frame: 2 years
description: Percentage of patients experiencing overall partial response (PR).
measure: Progressive Disease Rate
time frame: 2 years
description: Percentage of patients experiencing overall progressive disease (PD).
measure: Stable Disease Rate
time frame: 2 years
description: Percentage of patients experiencing overall stable disease (SD).
arm group label: No TP53/Rb1 Co-Mutation
arm group type: Active Comparator
description: HG-LCNEC tumor lacking the TP53/Rb1 co-mutation (non-small cell-like).
arm group label: TP53/Rb1 Co-Mutation Present
arm group type: Experimental
description: HG-LCNEC tumor with the TP53/Rb1 co-mutation.
intervention type: Other
intervention name: Treatment Specific for Non-Small Cell Carcinoma/Adenocarcinoma
description: Treatment assigned to targetable mutation. Or, for tumors that are by and large without any targetable mutation follow Large-Cell Neuroendocrine Carcinoma (NCCN) guideline-directed best front-line treatment for specific non-small cell carcinoma/adenocarcinoma.
arm group label: No TP53/Rb1 Co-Mutation
intervention type: Other
intervention name: Treatment for Small Cell Lung Cancer
description: Treatment assigned to a targetable mutation or the current standard-of-care regimen for the treatment of small cell lung cancer.
arm group label: TP53/Rb1 Co-Mutation Present
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Charles Kunos, MD
role: Principal Investigator
affiliation: University of Kentucky
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Kentucky
investigator full name: Charles Kunos
investigator title: Professor
mesh term: Carcinoma
mesh term: Carcinoma, Neuroendocrine
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 