<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/NCT03300843</url>
  </required_header>
  <id_info>
    <org_study_id>170177</org_study_id>
    <secondary_id>17-C-0177</secondary_id>
    <nct_id>NCT03300843</nct_id>
  </id_info>
  <brief_title>Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer</brief_title>
  <official_title>A Phase II Trial to Evaluate the Ability of a Dendritic Cell Vaccine to Immunize Melanoma or Epithelial Cancer Patients Against Defined Mutated Neoantigens Expressed by the Autologous Cancer</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>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Exomes are the parts of deoxyribonucleic acid (DNA) that make proteins. Researchers are&#xD;
      finding a way to read the letters in the exome. Incorrect letters are called mutations.&#xD;
      Tumors contain specific mutations. Researchers can find these mutations in tumors to make&#xD;
      treatments. Researchers want to use pieces of participants tumors to find the tumor-specific&#xD;
      mutations. They also will take participants white blood cells to make a vaccine that they&#xD;
      hope will shrink the tumors.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      To see if dendritic vaccine tumor-fighting cells are safe and can cause certain cancer tumors&#xD;
      to shrink.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Adults ages 18-70 who have metastatic melanoma or metastatic epithelial cancer&#xD;
&#xD;
      Design:&#xD;
&#xD;
      The first part of this study was done under protocol 03-C-0277. In that study, white blood&#xD;
      cells and pieces of participants' tumors were taken to make a vaccine.&#xD;
&#xD;
      In this study, participants will get a vaccine every 2 weeks for 8 weeks. It will be given&#xD;
      both in a vein and under the skin. At each visit, participants will have a physical exam and&#xD;
      have blood taken. They will talk about any side effects they have.&#xD;
&#xD;
      After treatment ends, participants will have many follow-up visits for the first year, then&#xD;
      once each year after that. Visits will last up to 2 days each. They will include lab tests,&#xD;
      imaging studies, and a physical exam. Blood will be taken at each visit. At the first&#xD;
      follow-up visit, participants may have leukapheresis, which they also had as part of protocol&#xD;
      03-C-0277. Participants may not have to return to the Clinical Center for these visits.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Therapeutic vaccination against cancer has proven very challenging with little clinical&#xD;
           benefit.&#xD;
&#xD;
        -  Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer&#xD;
           testis antigens, and overexpressed antigens. However negative selection in the thymus&#xD;
           against these normal nonmutated antigens severely limits the ability to generate high&#xD;
           avidity anti-cancer T cells. Such depletion can impair their antitumor activity and&#xD;
           limit tumor elimination.&#xD;
&#xD;
        -  The National Cancer Institute Surgery Branch (NCI SB) has developed a pipeline for the&#xD;
           identification of immunogenic T cell epitopes derived from neoantigens.&#xD;
&#xD;
        -  In recent studies, we identified the neoantigens recognized by tumor infiltrating&#xD;
           lymphocytes (TIL) that mediated regression in patients with metastatic cancer. Using&#xD;
           whole exome sequencing of a resected metastatic nodule followed by high throughput&#xD;
           immunologic screening, we were able to demonstrate that tumor regressions were&#xD;
           associated with the recognition by the administered TIL of unique somatic mutations that&#xD;
           occurred in the cancer.&#xD;
&#xD;
        -  We, therefore, aim to use this pipeline to identify immunogenic neoantigens from&#xD;
           epithelial cancer patients and to use these defined epitopes for a personalized&#xD;
           therapeutic dendritic cell (DC) vaccine.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      -Primary objectives:&#xD;
&#xD;
      --To determine the clinical response rate in patients with metastatic melanoma or epithelial&#xD;
      cancer who receive this DC vaccine&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Age greater than or equal to 18 and less than or equal to 70 years&#xD;
&#xD;
        -  Eastern Cooperative Oncology Group (ECOG) 0 - 2&#xD;
&#xD;
        -  Evaluable metastatic melanoma or epithelial cancer refractory to standard treatment&#xD;
&#xD;
        -  Metastatic melanoma or epithelial cancer lesion(s) that is resectable for TIL or in&#xD;
           selected cases, available peripheral blood mononuclear cells (PBMC).&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Patients with metastatic melanoma or epithelial cancer will undergo surgical resection&#xD;
           of tumor followed by exome and ribonucleic acid (RNA) sequencing to identify expressed&#xD;
           mutations (CONDUCTED UNDER THE National Cancer Institute Surgery Branch (NCI SB)&#xD;
           COMPANION PROTOCOL 03-c-0277).&#xD;
&#xD;
        -  Patients will undergo apheresis and DC will be cryopreserved for vaccine preparation.&#xD;
&#xD;
        -  Immunogenic neoantigens will be identified from TIL and PBMC by high throughput&#xD;
           immunologic screening using long peptides and tandem minigenes covering all mutated&#xD;
           epitopes.&#xD;
&#xD;
        -  Patient will be vaccinated with autologous mature dendritic cells loaded with long&#xD;
           peptides and minimal epitopes from defined neoantigens or highly expressed mutations in&#xD;
           tumor suppressor or driver genes.&#xD;
&#xD;
        -  DC will be administered intravenously and subcutaneously for four cycles at biweekly&#xD;
           intervals.&#xD;
&#xD;
        -  Blood samples will be taken every two weeks, and patients will be monitored for the&#xD;
           quantity and quality of circulating neoantigen-specific T cells.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    slow accrual&#xD;
  </why_stopped>
  <start_date type="Actual">April 11, 2018</start_date>
  <completion_date type="Actual">September 16, 2019</completion_date>
  <primary_completion_date type="Actual">July 9, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <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>Percentage of Patients Who Had a Clinical Response (Complete Response (CR) + Partial Response (PR)) to Treatment</measure>
    <time_frame>up to 6 months</time_frame>
    <description>Response was assessed by the RECIST v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With 2-3 Fold Increase From Baseline in Reactivity to Circulating Antigen-specific T Cells to the Mutated Peptide Compared to the Non-mutated Peptide</measure>
    <time_frame>Day 0, Day 14 (± 5 d), Day 28 (± 5 d), and Day 42 (± 5 d)</time_frame>
    <description>Enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immune absorbent spot (ELISpot) assays assessed reactivity to the mutated peptide compared to the non-mutated peptide. Differences of 2-3 fold in these assays over the baseline measurement are indicative of true biologic differences.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Serious and Non-serious Adverse Events</measure>
    <time_frame>Date treatment consent signed to date off study, approximately 6 months and 11 days</time_frame>
    <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Melanoma</condition>
  <condition>Gastrointestinal Cancer</condition>
  <condition>Breast Cancer</condition>
  <condition>Ovarian Cancer</condition>
  <condition>Pancreatic Cancer</condition>
  <arm_group>
    <arm_group_label>Peptide loaded dendritic cell vaccine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Peptide loaded dendritic cell vaccine</intervention_name>
    <description>On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.</description>
    <arm_group_label>Peptide loaded dendritic cell vaccine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Metastatic melanoma or epithelial cancer with at least one lesion that is resectable&#xD;
             or in selected cases, available peripheral blood mononuclear cells (PBMCs)&#xD;
&#xD;
          -  Measurable and evaluable metastatic disease per Response Evaluation Criteria in Solid&#xD;
             Tumors (RECIST) 1.1 criteria&#xD;
&#xD;
          -  Confirmation of the diagnosis of metastatic cancer by the Laboratory of Pathology of&#xD;
             National Cancer Institute (NCI).&#xD;
&#xD;
          -  All patients must be refractory to approved standard systemic therapy.&#xD;
&#xD;
          -  Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and&#xD;
             asymptomatic are eligible. Lesions that have been treated with stereotactic&#xD;
             radiosurgery must be clinically stable for one month after treatment for the patient&#xD;
             to be eligible. Patients with surgically resected brain metastases are eligible.&#xD;
&#xD;
          -  Greater than or equal to 18 years of age and less than or equal to 70 years of age.&#xD;
&#xD;
          -  Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0, 1, 2&#xD;
&#xD;
          -  Patients of both genders must be willing to practice birth control from the time of&#xD;
             enrollment on this study and for up to four months after treatment.&#xD;
&#xD;
          -  Serology:&#xD;
&#xD;
               -  Seronegative for Human Immunodeficiency Virus (HIV) antibody. (The experimental&#xD;
                  treatment being evaluated in this protocol depends on an intact immune system.&#xD;
                  Patients who are HIV seropositive can have decreased immune-competence and thus&#xD;
                  are less responsive to the experimental treatment and more susceptible to its&#xD;
                  toxicities.)&#xD;
&#xD;
               -  Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.&#xD;
                  If hepatitis C antibody test is positive, then the patient must be tested for the&#xD;
                  presence of antigen by reverse transcriptase polymerase chain reaction (RT-PCR)&#xD;
                  and be hepatitis C virus ribonucleic acid (HCV RNA) negative.&#xD;
&#xD;
          -  Hematology&#xD;
&#xD;
               -  Absolute neutrophil count greater than 1000/mm^3 without the support of&#xD;
                  filgrastim&#xD;
&#xD;
               -  White blood cell (WBC) greater than or equal to 3000/mm^3&#xD;
&#xD;
               -  Platelet count greater than or equal to 100,000/mm^3&#xD;
&#xD;
               -  Hemoglobin &gt; 8.0 g/dl. Subjects may be transfused to reach this cut-off.&#xD;
&#xD;
               -  Cluster of differentiation 4 (CD4) count &gt; 200/uL&#xD;
&#xD;
          -  Chemistry:&#xD;
&#xD;
               -  Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than&#xD;
                  5.0 x ULN&#xD;
&#xD;
               -  Serum Creatinine less than or equal to 1.6 mg/dl&#xD;
&#xD;
               -  Total bilirubin less than or equal to 2.0 mg/dl, except in patients with&#xD;
                  Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3.0&#xD;
                  mg/dl.&#xD;
&#xD;
          -  More than four weeks must have elapsed since any prior systemic therapy at the time&#xD;
             the patient receives the vaccine, and patients toxicities must have recovered to a&#xD;
             grade 1 or less (except for toxicities such as alopecia or vitiligo).&#xD;
&#xD;
        Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as&#xD;
        long as all toxicities have recovered to grade 1 or less.&#xD;
&#xD;
          -  Ability of subject to understand and the willingness to sign a written informed&#xD;
             consent document.&#xD;
&#xD;
          -  Subjects must be co-enrolled On protocol 03-C-0277.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Women of child-bearing potential who are pregnant or breastfeeding because of the&#xD;
             potentially dangerous effects of the treatment on the fetus or infant.&#xD;
&#xD;
          -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency&#xD;
             Disease).&#xD;
&#xD;
          -  Concurrent opportunistic infections (The experimental treatment being evaluated in&#xD;
             this protocol depends on an intact immune system. Patients who have decreased immune&#xD;
             competence may be less responsive to the experimental treatment and more susceptible&#xD;
             to its toxicities).&#xD;
&#xD;
          -  Active systemic infections (requiring anti-infective treatment), coagulation disorders&#xD;
             or any other active or uncompensated major medical illnesses.&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Steven A Rosenberg, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <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>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol. 2009 Dec;9(12):833-44. doi: 10.1038/nri2669.</citation>
    <PMID>19935803</PMID>
  </reference>
  <reference>
    <citation>Abramson J, Giraud M, Benoist C, Mathis D. Aire's partners in the molecular control of immunological tolerance. Cell. 2010 Jan 8;140(1):123-35. doi: 10.1016/j.cell.2009.12.030.</citation>
    <PMID>20085707</PMID>
  </reference>
  <reference>
    <citation>Bos R, Marquardt KL, Cheung J, Sherman LA. Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment. Oncoimmunology. 2012 Nov 1;1(8):1239-1247. doi: 10.4161/onci.21285.</citation>
    <PMID>23243587</PMID>
  </reference>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>October 3, 2017</study_first_submitted>
  <study_first_submitted_qc>October 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 4, 2017</study_first_posted>
  <results_first_submitted>November 19, 2019</results_first_submitted>
  <results_first_submitted_qc>November 19, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">December 13, 2019</results_first_posted>
  <last_update_submitted>November 19, 2019</last_update_submitted>
  <last_update_submitted_qc>November 19, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 13, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cancer Institute (NCI)</investigator_affiliation>
    <investigator_full_name>Steven Rosenberg, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Cell Therapy</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>Vaccines</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Gastrointestinal Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 26, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03300843/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 4, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03300843/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Peptide Loaded Dendritic Cell Vaccine</title>
          <description>Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42&#xD;
Peptide loaded dendritic cell vaccine: On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Peptide Loaded Dendritic Cell Vaccine</title>
          <description>Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42&#xD;
Peptide loaded dendritic cell vaccine: On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="1"/>
          </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_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62.0"/>
                  </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="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" 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_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Patients Who Had a Clinical Response (Complete Response (CR) + Partial Response (PR)) to Treatment</title>
        <description>Response was assessed by the RECIST v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.</description>
        <time_frame>up to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Peptide Loaded Dendritic Cell Vaccine</title>
            <description>Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42&#xD;
Peptide loaded dendritic cell vaccine: On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients Who Had a Clinical Response (Complete Response (CR) + Partial Response (PR)) to Treatment</title>
          <description>Response was assessed by the RECIST v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With 2-3 Fold Increase From Baseline in Reactivity to Circulating Antigen-specific T Cells to the Mutated Peptide Compared to the Non-mutated Peptide</title>
        <description>Enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immune absorbent spot (ELISpot) assays assessed reactivity to the mutated peptide compared to the non-mutated peptide. Differences of 2-3 fold in these assays over the baseline measurement are indicative of true biologic differences.</description>
        <time_frame>Day 0, Day 14 (± 5 d), Day 28 (± 5 d), and Day 42 (± 5 d)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Peptide Loaded Dendritic Cell Vaccine</title>
            <description>Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42&#xD;
Peptide loaded dendritic cell vaccine: On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With 2-3 Fold Increase From Baseline in Reactivity to Circulating Antigen-specific T Cells to the Mutated Peptide Compared to the Non-mutated Peptide</title>
          <description>Enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immune absorbent spot (ELISpot) assays assessed reactivity to the mutated peptide compared to the non-mutated peptide. Differences of 2-3 fold in these assays over the baseline measurement are indicative of true biologic differences.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mutated peptide Day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mutated peptide Day 14</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mutated peptide Day 28</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mutated peptide Day 42</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Mutated peptide Day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Mutated peptide Day 14</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Mutated peptide Day 28</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Mutated peptide Day 56</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Serious and Non-serious Adverse Events</title>
        <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
        <time_frame>Date treatment consent signed to date off study, approximately 6 months and 11 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Peptide Loaded Dendritic Cell Vaccine</title>
            <description>Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42&#xD;
Peptide loaded dendritic cell vaccine: On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Serious and Non-serious Adverse Events</title>
          <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Date treatment consent signed to date off study, approximately 6 months and 11 days.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Peptide Loaded Dendritic Cell Vaccine</title>
          <description>Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42&#xD;
Peptide loaded dendritic cell vaccine: On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.</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="1"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin induration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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. Steven A. Rosenberg</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>240-858-3080</phone>
      <email>steven-rosenberg@nih.gov</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/NCT03300843
org study id: 170177
secondary id: 17-C-0177
nct id: NCT03300843
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Exomes are the parts of deoxyribonucleic acid (DNA) that make proteins. Researchers are
      finding a way to read the letters in the exome. Incorrect letters are called mutations.
      Tumors contain specific mutations. Researchers can find these mutations in tumors to make
      treatments. Researchers want to use pieces of participants tumors to find the tumor-specific
      mutations. They also will take participants white blood cells to make a vaccine that they
      hope will shrink the tumors.

      Objectives:

      To see if dendritic vaccine tumor-fighting cells are safe and can cause certain cancer tumors
      to shrink.

      Eligibility:

      Adults ages 18-70 who have metastatic melanoma or metastatic epithelial cancer

      Design:

      The first part of this study was done under protocol 03-C-0277. In that study, white blood
      cells and pieces of participants' tumors were taken to make a vaccine.

      In this study, participants will get a vaccine every 2 weeks for 8 weeks. It will be given
      both in a vein and under the skin. At each visit, participants will have a physical exam and
      have blood taken. They will talk about any side effects they have.

      After treatment ends, participants will have many follow-up visits for the first year, then
      once each year after that. Visits will last up to 2 days each. They will include lab tests,
      imaging studies, and a physical exam. Blood will be taken at each visit. At the first
      follow-up visit, participants may have leukapheresis, which they also had as part of protocol
      03-C-0277. Participants may not have to return to the Clinical Center for these visits.
Background:

        -  Therapeutic vaccination against cancer has proven very challenging with little clinical
           benefit.

        -  Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer
           testis antigens, and overexpressed antigens. However negative selection in the thymus
           against these normal nonmutated antigens severely limits the ability to generate high
           avidity anti-cancer T cells. Such depletion can impair their antitumor activity and
           limit tumor elimination.

        -  The National Cancer Institute Surgery Branch (NCI SB) has developed a pipeline for the
           identification of immunogenic T cell epitopes derived from neoantigens.

        -  In recent studies, we identified the neoantigens recognized by tumor infiltrating
           lymphocytes (TIL) that mediated regression in patients with metastatic cancer. Using
           whole exome sequencing of a resected metastatic nodule followed by high throughput
           immunologic screening, we were able to demonstrate that tumor regressions were
           associated with the recognition by the administered TIL of unique somatic mutations that
           occurred in the cancer.

        -  We, therefore, aim to use this pipeline to identify immunogenic neoantigens from
           epithelial cancer patients and to use these defined epitopes for a personalized
           therapeutic dendritic cell (DC) vaccine.

      Objectives:

      -Primary objectives:

      --To determine the clinical response rate in patients with metastatic melanoma or epithelial
      cancer who receive this DC vaccine

      Eligibility:

        -  Age greater than or equal to 18 and less than or equal to 70 years

        -  Eastern Cooperative Oncology Group (ECOG) 0 - 2

        -  Evaluable metastatic melanoma or epithelial cancer refractory to standard treatment

        -  Metastatic melanoma or epithelial cancer lesion(s) that is resectable for TIL or in
           selected cases, available peripheral blood mononuclear cells (PBMC).

      Design:

        -  Patients with metastatic melanoma or epithelial cancer will undergo surgical resection
           of tumor followed by exome and ribonucleic acid (RNA) sequencing to identify expressed
           mutations (CONDUCTED UNDER THE National Cancer Institute Surgery Branch (NCI SB)
           COMPANION PROTOCOL 03-c-0277).

        -  Patients will undergo apheresis and DC will be cryopreserved for vaccine preparation.

        -  Immunogenic neoantigens will be identified from TIL and PBMC by high throughput
           immunologic screening using long peptides and tandem minigenes covering all mutated
           epitopes.

        -  Patient will be vaccinated with autologous mature dendritic cells loaded with long
           peptides and minimal epitopes from defined neoantigens or highly expressed mutations in
           tumor suppressor or driver genes.

        -  DC will be administered intravenously and subcutaneously for four cycles at biweekly
           intervals.

        -  Blood samples will be taken every two weeks, and patients will be monitored for the
           quantity and quality of circulating neoantigen-specific T cells.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Patients Who Had a Clinical Response (Complete Response (CR) + Partial Response (PR)) to Treatment
time frame: up to 6 months
description: Response was assessed by the RECIST v1.1. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
measure: Number of Participants With 2-3 Fold Increase From Baseline in Reactivity to Circulating Antigen-specific T Cells to the Mutated Peptide Compared to the Non-mutated Peptide
time frame: Day 0, Day 14 (± 5 d), Day 28 (± 5 d), and Day 42 (± 5 d)
description: Enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immune absorbent spot (ELISpot) assays assessed reactivity to the mutated peptide compared to the non-mutated peptide. Differences of 2-3 fold in these assays over the baseline measurement are indicative of true biologic differences.
measure: Number of Participants With Serious and Non-serious Adverse Events
time frame: Date treatment consent signed to date off study, approximately 6 months and 11 days
description: Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
arm group label: Peptide loaded dendritic cell vaccine
arm group type: Experimental
description: Peptide loaded dendritic cell vaccine on days 0, 14, 28, and 42
intervention type: Biological
intervention name: Peptide loaded dendritic cell vaccine
description: On days 0, 14 (+/- 5 days), 28 (+/- 5 days), and 42 (+/- 5 days). The vaccine will be administered as both an intravenous (IV) infusion and a subcutaneous (SQ) injection. The total dose will be divided equally between intravenous (IV) and SQ containing 1.0E7 to 8.0E7 cells per cycle depending upon the manufacturing yield.
arm group label: Peptide loaded dendritic cell vaccine
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Steven A Rosenberg, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
citation: Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol. 2009 Dec;9(12):833-44. doi: 10.1038/nri2669.
PMID: 19935803
citation: Abramson J, Giraud M, Benoist C, Mathis D. Aire's partners in the molecular control of immunological tolerance. Cell. 2010 Jan 8;140(1):123-35. doi: 10.1016/j.cell.2009.12.030.
PMID: 20085707
citation: Bos R, Marquardt KL, Cheung J, Sherman LA. Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment. Oncoimmunology. 2012 Nov 1;1(8):1239-1247. doi: 10.4161/onci.21285.
PMID: 23243587
responsible party type: Principal Investigator
investigator affiliation: National Cancer Institute (NCI)
investigator full name: Steven Rosenberg, M.D.
investigator title: Principal Investigator
mesh term: Melanoma
mesh term: Gastrointestinal Neoplasms
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 