<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/NCT04411134</url>
  </required_header>
  <id_info>
    <org_study_id>200093</org_study_id>
    <secondary_id>20-C-0093</secondary_id>
    <nct_id>NCT04411134</nct_id>
  </id_info>
  <brief_title>E7 TCR T Cell Immunotherapy for High-Grade Cervical Intraepithelial Neoplasia</brief_title>
  <official_title>A Phase I Study of E7 TCR T Cell Immunotherapy for High-Grade Cervical Intraepithelial Neoplasia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Human papillomavirus (HPV) can lead to High-Grade Cervical Intraepithelial Neoplasia (CIN&#xD;
      2,3). This type of lesion has a high risk of becoming cancer. T cells are part of the immune&#xD;
      system. A new type of treatment involves modifying these cells and injecting them into the&#xD;
      lesions to shrink them.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To test if injecting a type of treatment directly into cervical lesions can be safely given&#xD;
      as therapy for high-grade CIN.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People ages 21 and older with CIN 2,3 caused by HPV-16&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened over at least 2 visits with:&#xD;
&#xD;
      Tumor sample&#xD;
&#xD;
      Blood and urine tests&#xD;
&#xD;
      Medical and medication history&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Pelvic exam and colposcopy to look at the cervix&#xD;
&#xD;
      Participants will have a baseline visit. They may be admitted to the hospital. They may&#xD;
      receive a large catheter inserted into a vein. They will have a vein assessment.&#xD;
&#xD;
      Before they receive treatment, participants will have a biopsy of the cervix. They will have&#xD;
      leukapheresis. Blood will be removed through a needle in the arm, circulated through a&#xD;
      machine that takes out the while blood cells, then returned through a needle in the other&#xD;
      arm. A central catheter may also be used.&#xD;
&#xD;
      Participants will have the modified cells injected directly into their cervical lesions. They&#xD;
      will recover in the hospital for 1-2 days.&#xD;
&#xD;
      Participants will have follow-up visits 2 weeks, 31 days, 6 weeks, and 12 weeks after&#xD;
      treatment. They may receive a second injection at the 31-day visit.&#xD;
&#xD;
      Participants will be contacted once a year for 5 years after treatment. They will be followed&#xD;
      for up to 15 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Cervical Intraepithelial Neoplasia (CIN) is caused by persistent infection with the&#xD;
           Human Papillomavirus (HPV).&#xD;
&#xD;
        -  High-grade lesions are common, affecting 5% of the female population in the United&#xD;
           States, and are more likely to progress to cervical cancer.&#xD;
&#xD;
        -  Surgical and ablative therapies are effective but can lead to long-term morbidity. New&#xD;
           treatment modalities are needed.&#xD;
&#xD;
        -  E7 TCR T cells have demonstrated safety and clinical activity in treatment-refractory&#xD;
           metastatic HPV+ cancers.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To determine the safety of intralesional injection of E7 TCR T cells as therapy for high-&#xD;
      grade CIN.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Patients greater than or equal to 21 years of age with HPV16-associated, high-grade CIN.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  This is a phase I clinical trial with a 3+3 dose escalation design.&#xD;
&#xD;
        -  Patients will receive intralesional injections of E7 TCR T cells.&#xD;
&#xD;
        -  Patients will not receive a conditioning chemotherapy regimen or systemic aldesleukin.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Closed based on the lack of perceived clinical activity observed from a different study&#xD;
    treating a similar patient population with same study agent.&#xD;
  </why_stopped>
  <start_date type="Actual">May 28, 2020</start_date>
  <completion_date type="Actual">July 14, 2020</completion_date>
  <primary_completion_date type="Actual">July 14, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To determine the safety of intralesional injection of E7 TCR T cell therapy for highgrade CIN</measure>
    <time_frame>3 months</time_frame>
    <description>The fraction who experience a DLT based on the dose level and cell administration within the dose level will be determined and reported.The analysis will be entirely descriptive.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Cervical Intraepithelial Neoplasia</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Approximately 3x10^8 or 1.5x10^9 E7 TCR T cells will be injected on day 0 and 1.5x10^9 E7 TCR T cells on day 31 (2 escalating dose levels)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The MTD from among dose level 1 and dose level 2</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>E7 TCR</intervention_name>
    <description>Approximately 3x10^8 or 1.5x10^9 E7 TCR T cells will be injected on day 0 and 1.5x10^9 E7 TCR T cells on day 31 (2 escalating dose levels)</description>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_label>Arm 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients must have histologically confirmed high-grade cervical intraepithelial&#xD;
             neoplasia (CIN 2,3). Confirmation of high-grade cervical intraepithelial neoplasia&#xD;
             (pathology report from outside institution is sufficient). Pathology confirming&#xD;
             high-grade CIN must be within 3 months prior to initiation of study therapy. If&#xD;
             needed, confirmatory biopsy of lesion(s) may be performed.&#xD;
&#xD;
          -  HPV16+ CIN 2,3 and HLA-A*02:01 HLA type&#xD;
&#xD;
          -  Patients may be treatment-naive or have received previous treatment for high-grade&#xD;
             CIN. Patients who have received previous treatment are eligible if prior treatment was&#xD;
             greater than or equal to 3 months before first dose of E7 TCR T cells and there is&#xD;
             pathological confirmation of recurrent or persistent disease. If needed, confirmatory&#xD;
             biopsy of lesion(s) may be performed.&#xD;
&#xD;
          -  Patients can have either one lesion or multiple lesions with at least one lesion being&#xD;
             visible on colposcopy to help facilitate intralesional administration of E7 TCR T&#xD;
             cells.&#xD;
&#xD;
          -  Age greater than or equal to 21 years. Because treatment for this disease is not&#xD;
             recommended in patients &lt;21 years of age, children and adolescents &lt;21 years old are&#xD;
             excluded from this study.&#xD;
&#xD;
          -  ECOG performance status greater than or equal to 2.&#xD;
&#xD;
          -  Patients must have adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  leukocytes greater than or equal to 3,000/mcL&#xD;
&#xD;
               -  absolute neutrophil count greater than or equal to 1,500/mcL&#xD;
&#xD;
               -  platelets greater than or equal to 100,000/mcL&#xD;
&#xD;
               -  total bilirubin within 1.5X normal institutional limits&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of&#xD;
                  normal&#xD;
&#xD;
               -  creatinine within normal institutional limits&#xD;
&#xD;
               -  creatinine clearance Calculated creatinine clearance (CrCl) &gt;50mL/min/1.73m^2 for&#xD;
                  patient with creatinine levels above institutional normal (by the Chronic Kidney&#xD;
                  Disease Epidemiology Collaboration (CKD-EPI) equation)&#xD;
&#xD;
          -  Women of child-bearing potential must have a negative pregnancy test because E7 TCR T&#xD;
             cells have unknown potential for teratogenic or abortifacient effects. Women of&#xD;
             childbearing potential are defined as all women who are not post-menopausal or who&#xD;
             have not had a hysterectomy. Postmenopausal will be defined as women over the age of&#xD;
             55 who have not had a menstrual period in at least 1 year.&#xD;
&#xD;
          -  The effects of E7 TCR T cells on the developing human fetus are unknown. For this&#xD;
             reason, women of child-bearing potential must agree to use adequate contraception&#xD;
             (intrauterine device, hormonal or barrier method of birth control, abstinence, tubal&#xD;
             ligation or vasectomy) prior to study entry and for up to 4 months after treatment.&#xD;
             Should a woman become pregnant or suspect she is pregnant while she is participating&#xD;
             in this study, she should inform her treating physician immediately.&#xD;
&#xD;
          -  Seronegative for HIV antibody. The experimental treatment being evaluated in this&#xD;
             protocol depends on an intact immune system. Patients who are HIV seropositive can&#xD;
             have decreased immune-competence and thus be less responsive to the experimental&#xD;
             treatment.&#xD;
&#xD;
          -  Seronegative for hepatitis B antigen and hepatitis C antibody. If hepatitis C antibody&#xD;
             test is positive, then the patient must be tested for the presence of antigen by&#xD;
             RT-PCR and be HCV RNA negative.&#xD;
&#xD;
          -  Must be willing to participate in Gene Therapy Long Term Follow up Protocol, which&#xD;
             will follow patients for up to 15 years per Food and Drug Administration (FDA)&#xD;
             requirements.&#xD;
&#xD;
          -  Ability of subject to understand and the willingness to sign a written informed&#xD;
             consent document.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, active infection,&#xD;
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or&#xD;
             psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements.&#xD;
&#xD;
          -  Because there is an unknown but potential risk for adverse events in nursing infants&#xD;
             secondary to treatment of the mother with E7 TCR T cells, breastfeeding should be&#xD;
             discontinued if the mother is treated with E7 TCR T cells. These potential risks may&#xD;
             also apply to other agents used in this study.&#xD;
&#xD;
          -  Patients with any form of systemic immunodeficiency, including acquired deficiency&#xD;
             such as HIV or primary immunodeficiency such as Severe Combined Immunodeficiency&#xD;
             Disease, are ineligible. The experimental treatment being evaluated in this protocol&#xD;
             depends on an intact immune system. Patients who have decreased immune competence may&#xD;
             be less responsive to the treatment.&#xD;
&#xD;
          -  Patients on immunosuppressive drugs including systemic corticosteroids (inhaled or&#xD;
             intranasal corticosteroids are allowed).&#xD;
&#xD;
          -  Patients with a second active invasive cancer are not eligible.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christian S Hinrichs, 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>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2020-C-0093.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>May 30, 2020</study_first_submitted>
  <study_first_submitted_qc>May 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 2, 2020</study_first_posted>
  <last_update_submitted>July 14, 2020</last_update_submitted>
  <last_update_submitted_qc>July 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 15, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>T Cell Receptor</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>Human Papillomavirus</keyword>
  <keyword>Intralesional Injections</keyword>
  <keyword>Cervical Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Carcinoma in Situ</mesh_term>
    <mesh_term>Uterine Cervical Dysplasia</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04411134
org study id: 200093
secondary id: 20-C-0093
nct id: NCT04411134
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Human papillomavirus (HPV) can lead to High-Grade Cervical Intraepithelial Neoplasia (CIN
      2,3). This type of lesion has a high risk of becoming cancer. T cells are part of the immune
      system. A new type of treatment involves modifying these cells and injecting them into the
      lesions to shrink them.

      Objective:

      To test if injecting a type of treatment directly into cervical lesions can be safely given
      as therapy for high-grade CIN.

      Eligibility:

      People ages 21 and older with CIN 2,3 caused by HPV-16

      Design:

      Participants will be screened over at least 2 visits with:

      Tumor sample

      Blood and urine tests

      Medical and medication history

      Physical exam

      Pelvic exam and colposcopy to look at the cervix

      Participants will have a baseline visit. They may be admitted to the hospital. They may
      receive a large catheter inserted into a vein. They will have a vein assessment.

      Before they receive treatment, participants will have a biopsy of the cervix. They will have
      leukapheresis. Blood will be removed through a needle in the arm, circulated through a
      machine that takes out the while blood cells, then returned through a needle in the other
      arm. A central catheter may also be used.

      Participants will have the modified cells injected directly into their cervical lesions. They
      will recover in the hospital for 1-2 days.

      Participants will have follow-up visits 2 weeks, 31 days, 6 weeks, and 12 weeks after
      treatment. They may receive a second injection at the 31-day visit.

      Participants will be contacted once a year for 5 years after treatment. They will be followed
      for up to 15 years.
Background:

        -  Cervical Intraepithelial Neoplasia (CIN) is caused by persistent infection with the
           Human Papillomavirus (HPV).

        -  High-grade lesions are common, affecting 5% of the female population in the United
           States, and are more likely to progress to cervical cancer.

        -  Surgical and ablative therapies are effective but can lead to long-term morbidity. New
           treatment modalities are needed.

        -  E7 TCR T cells have demonstrated safety and clinical activity in treatment-refractory
           metastatic HPV+ cancers.

      Objectives:

      - To determine the safety of intralesional injection of E7 TCR T cells as therapy for high-
      grade CIN.

      Eligibility:

      - Patients greater than or equal to 21 years of age with HPV16-associated, high-grade CIN.

      Design:

        -  This is a phase I clinical trial with a 3+3 dose escalation design.

        -  Patients will receive intralesional injections of E7 TCR T cells.

        -  Patients will not receive a conditioning chemotherapy regimen or systemic aldesleukin.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: To determine the safety of intralesional injection of E7 TCR T cell therapy for highgrade CIN
time frame: 3 months
description: The fraction who experience a DLT based on the dose level and cell administration within the dose level will be determined and reported.The analysis will be entirely descriptive.
arm group label: Arm 1
arm group type: Experimental
description: Approximately 3x10^8 or 1.5x10^9 E7 TCR T cells will be injected on day 0 and 1.5x10^9 E7 TCR T cells on day 31 (2 escalating dose levels)
arm group label: Arm 2
arm group type: Experimental
description: The MTD from among dose level 1 and dose level 2
intervention type: Biological
intervention name: E7 TCR
description: Approximately 3x10^8 or 1.5x10^9 E7 TCR T cells will be injected on day 0 and 1.5x10^9 E7 TCR T cells on day 31 (2 escalating dose levels)
arm group label: Arm 1
arm group label: Arm 2
criteria: 
gender: Female
minimum age: 21 Years
maximum age: N/A
healthy volunteers: No
last name: Christian S Hinrichs, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2020-C-0093.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Carcinoma in Situ
mesh term: Uterine Cervical Dysplasia