<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/NCT02211027</url>
  </required_header>
  <id_info>
    <org_study_id>13-160</org_study_id>
    <nct_id>NCT02211027</nct_id>
  </id_info>
  <brief_title>Biological Vaccine: Semi-allogeneic Human Fibroblasts (MRC-5) Transfected With DNA</brief_title>
  <official_title>Active Immunization of Patients With Head and Neck Squamous Cell Carcinoma (HNSCC) Using Fibroblasts Transfected With DNA From Autologous Tumor</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Robert Ferris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Immune Cell Therapy Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypothesis The incidence of toxicity in patients receiving the tumor DNA-transfected&#xD;
      fibroblast vaccine will be acceptably low and the immunologic response rate sufficiently high&#xD;
      to warrant further study of this therapy&#xD;
&#xD;
      The study of the vaccine will proceed in two stages after the method of Simon (102). In the&#xD;
      first stage, 15 patients will be accrued and treated. If two or fewer objective immunologic&#xD;
      responses occur, the study will be terminated. If 3 or more responses are observed, the study&#xD;
      will proceed to the second stage, accruing an additional 22 patients. If the second stage is&#xD;
      complete and a total of 9 or more immunologic responses are observed among the 37 patients&#xD;
      treated, the treatment response rate for the vaccine will be considered high enough to&#xD;
      warrant further study. Conversely, if the evaluation of the vaccine concludes at the first&#xD;
      stage, or if 8 or fewer total immunologic responses occur after completing the second stage,&#xD;
      the vaccine will not be considered for further study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single institution open-label phase Ib clinical trial designed to determine the&#xD;
      safety of immunization of patients with resected Head and Neck Squamous Cell Carcinoma&#xD;
      (HNSCC) with lethally irradiated semi-allogeneic human fibroblasts (MRC-5) transfected with&#xD;
      DNA derived from the subject's own tumor and to measure the immune response to the autologous&#xD;
      tumor vaccine.&#xD;
&#xD;
      Briefly, the plan is to use a two-stage trial design and to initially enroll 15 patients with&#xD;
      Head and Neck Squamous Cell Carcinoma (HNSCC). The patients will undergo surgical resection&#xD;
      to provide complete removal of the primary lesion with negative gross and microscopic&#xD;
      margins. A portion of the primary tumor specimen not necessary for the pathologic diagnosis&#xD;
      will be obtained to serve as a source of DNA for preparing the vaccine. Each DNA-based&#xD;
      vaccine will contain 1 x 10e7 DNA-transfected human allogeneic fibroblasts. The vaccine will&#xD;
      be lethally irradiated before it is used for immunization. It will be administered&#xD;
      intradermally in the Outpatient Clinic for a total of four vaccinations delivered at weekly&#xD;
      intervals.&#xD;
&#xD;
      Patients delayed-type hypersensitivity (DTH) responses will be tested but will not be an&#xD;
      eligibility criterion. Immunologic response to the vaccine will be evaluated. If there is no&#xD;
      evidence of toxicity, and &gt;3 of the 15 initial patients show immunologic response, the second&#xD;
      stage of the study will be opened for accrual of 22 patients.&#xD;
&#xD;
      To determine patient's response to the DNA-based vaccines, the frequency of T cells reactive&#xD;
      with recipient cells transfected with the autologous tumor DNA will be measured by ELISPOT&#xD;
      for IFN-y and compared with the response to non-transfected fibroblasts prior to and after&#xD;
      vaccination. All patients will be monitored for Immunologic response by assays include&#xD;
      ELISPOT, flow cytometry for lymphocyte markers, Annexin V binding, TcR expression, caspase3&#xD;
      activity and serum antibodies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <start_date>September 2016</start_date>
  <completion_date type="Anticipated">December 2028</completion_date>
  <primary_completion_date type="Anticipated">October 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Immunization Safety</measure>
    <time_frame>2.5 years</time_frame>
    <description>Toxicity will be monitored continuously from the first vaccination through the 6 month post follow up study visit for each subject.&#xD;
Patients will have a follow-up visit at 1 week after last vaccination (day 29, off treatment), at 1 month, 3 months and 6 months after last vaccination or after removal from study or until death, whichever occurs first. After the 6 month follow-up visit, subjects will be followed for survival only (no additional clinical trial site visits). Patients removed from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.&#xD;
All subjects should be enrolled within 2 years and follow up studies complete within 3 years.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Immunologic Response Rate to the the tumor DNA-transfected fibroblast vaccine</measure>
    <time_frame>2.5 years</time_frame>
    <description>Immunologic evidence of a response to the DNA-based vaccine will depend on the results of ELISPOT assays performed at five to seven time points: pre-surgery, pre-vaccine (either at the day -28 or Day 1 prior to vaccination), on day 15, on day 29, 1 month, 3 months (if clinically indicated at 1 and 3 months) and at the 6 month post treatment follow-up appointment. A significant difference in the frequency of vaccine reactive or anti-tumor-reactive T cells between pre- and post-vaccine determinations will be considered as a positive immune response to the vaccine.&#xD;
Additionally, immune competence and the presence/absence of immune suppression will be evaluated before and after vaccine administration. The ability of DNA-based vaccines to reverse or diminish demonstrated effects in signaling defects, lymphocyte apoptosis or proportions of T(reg) in the peripheral circulation will be measured but will not be used as a criterion for evaluation of the immune response.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Immune competence</measure>
    <time_frame>2.5 years</time_frame>
    <description>Immune competence and the presence/absence of immune suppression will be evaluated before and after vaccine administration and at the 6 month follow-up visit. The ability of DNA-based vaccines to reverse or diminish demonstrated effects in signaling defects, lymphocyte apoptosis or proportions of T(reg) in the peripheral circulation will be measured but will not be used as a criterion for evaluation of the immune response.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Head and Neck Squamous Cell Carcinoma (HNSCC)</condition>
  <arm_group>
    <arm_group_label>Vaccine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The vaccine is composed of lethally irradiated semi-allogenic human fibroblasts (MRC-5) transfected with genomic tumor DNA from the patients own tumor.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Semi-allogenic human fibroblast (MRC-5) transfected with DNA</intervention_name>
    <description>Each vaccination consists of up to 1 x 10e7 (not less than 7 x 10e6) DNA-transfected irradiated fibroblasts. Each vaccination will be administered intradermally using a 1 mL syringe and a 25 gauge needle.The first immunization will be administered at least 12 weeks after surgery or completion of adjuvant chemotherapy and/or radiotherapy.Three additional vaccines will be administered once a week for a total of four vaccines.&#xD;
Patients will have vaccinations administered at 4 different sites as follows:&#xD;
Site #1: Right arm Site #2: Left arm Site #3: Right thigh Site #4: Left thigh. Approximately equal numbers of transfected fibroblasts will be administered at each site.</description>
    <arm_group_label>Vaccine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pathological stage I-IVa HNSCC&#xD;
&#xD;
          -  The subject must have a complete removal of the primary HNSCC lesion with negative&#xD;
             gross and microscopic margins. Documentation of margins by frozen sections at surgery&#xD;
             is recommended. Patients who have already had surgery and have available banked tumor&#xD;
             samples can be enrolled AFTER surgery.&#xD;
&#xD;
          -  At least 18 years of age.&#xD;
&#xD;
          -  Karnofsky performance status &gt;/= 70&#xD;
&#xD;
          -  Adequate hematologic function:&#xD;
&#xD;
          -  Absolute neutrophil count &gt; 1,000/mm3&#xD;
&#xD;
          -  Absolute lymphocyte count &gt; 1,000/mm3&#xD;
&#xD;
          -  Hemoglobin &gt; 9 g/dL&#xD;
&#xD;
          -  Platelets &gt; 100,000/mm3&#xD;
&#xD;
          -  Liver function tests:&#xD;
&#xD;
          -  Bilirubin (total) &lt; /=1.7 mg/dL&#xD;
&#xD;
          -  Alkaline phosphatase &lt; 252 u/L&#xD;
&#xD;
          -  SGOT &lt; 108 u/L&#xD;
&#xD;
          -  Kidney profile:&#xD;
&#xD;
          -  Serum electrolytes&#xD;
&#xD;
          -  Sodium 136-146 mEq/L&#xD;
&#xD;
          -  Potassium 3.5-5.0 mEq/L&#xD;
&#xD;
          -  Bicarbonate 21-31 mEq/L&#xD;
&#xD;
          -  Chloride 98-107 mmol/L&#xD;
&#xD;
          -  Serum creatinine &lt; 3 x ULN&#xD;
&#xD;
          -  BUN 8-26 mg/dL&#xD;
&#xD;
          -  At least a 12 week interval should have elapsed between prior surgery, radiation&#xD;
             therapy, chemotherapy or any other treatment and the first vaccination. Patients&#xD;
             should have recovered from surgery and adjuvant treatment.&#xD;
&#xD;
          -  The effects of the tumor DNA-transfected fibroblast vaccine on the developing human&#xD;
             fetus are unknown. For this reason women of child-bearing potential must agree to use&#xD;
             adequate contraception (hormonal or barrier method of birth control; abstinence) prior&#xD;
             to study entry, for the duration of study participation and for 4 months after the&#xD;
             last dose of the study vaccine, even if oral contraceptives are used. Should a woman&#xD;
             become pregnant or suspect she is pregnant while she or her partner is participating&#xD;
             in this study, she should inform her treating physician immediately. Men treated or&#xD;
             enrolled on this protocol must also agree to use adequate contraception prior to the&#xD;
             study, for the duration of study participation, and 4 months after completion of the&#xD;
             tumor DNA-transfected fibroblast vaccine administration.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients will be EXCLUDED from participation in the study if any of the following apply:&#xD;
&#xD;
          -  One or more of the Inclusion Criteria are not met.&#xD;
&#xD;
          -  A significant history or current evidence of cardiac disease including, but not&#xD;
             limited to: congestive heart failure, coronary artery disease, angina pectoris,&#xD;
             uncontrolled hypertension, serious arrhythmias or myocardial infarction within the&#xD;
             previous six months.&#xD;
&#xD;
          -  Evidence of ongoing or active infection requiring antibiotic therapy.&#xD;
&#xD;
          -  Active intracranial metastases. Patients with previously resected intracranial disease&#xD;
             and/or previously irradiated intracranial metastases that have been clinically stable&#xD;
             for four weeks are eligible.&#xD;
&#xD;
          -  Pregnant or lactating women. Pregnant women are excluded from this study. Women of&#xD;
             childbearing potential must have a negative pregnancy test per standard of care prior&#xD;
             to the surgery for tumor removal. A second pregnancy test must be performed 7 days&#xD;
             prior to the first vaccination and must be negative. Because there is an unknown but&#xD;
             potential risk for adverse events in nursing infants secondary to treatment of the&#xD;
             mother, breastfeeding should be discontinued if the mother is treated on study.&#xD;
&#xD;
          -  Patients requiring systemic corticosteroids (unless patients have had no&#xD;
             corticosteroids within 4 weeks prior to start of study).&#xD;
&#xD;
          -  Autoimmune disease including, but not limited to, rheumatoid arthritis, systemic lupus&#xD;
             erythematous, multiple sclerosis, or ankylosing spondylitis.&#xD;
&#xD;
          -  Patients who have post-obstructive pneumonia or other serious infection at the time of&#xD;
             registration or other serious underlying medical condition that would impair the&#xD;
             ability of the patient to receive protocol treatment.&#xD;
&#xD;
          -  No prior malignancy is allowed except for adequately treated basal cell or squamous&#xD;
             cell skin cancer, in situ cervical cancer, or other cancer from which the patient has&#xD;
             been disease-free for at least 5 years prior to registration.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to psychiatric&#xD;
             illness/social situations that would limit compliance with study requirements.&#xD;
&#xD;
          -  HIV-positive patients receiving combination anti-retroviral therapy are excluded from&#xD;
             the study. HIV testing will be performed in patients receiving combination&#xD;
             anti-retroviral therapy when indicated per medical records review.&#xD;
&#xD;
          -  Patients with clinical symptoms of Hepatitis B and/or Hepatitis C will be tested, if&#xD;
             clinically indicated per medical records review. Positive results will be an exclusion&#xD;
             criteria&#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>Robert L Ferris, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Professor of Otolaryngology, Eye &amp; Ear Institute of the University of Pittsburgh Medical Center.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Pittsburgh Medical Center Presbyterian Hospital</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Cancer Institute-Hillman Cancer Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Of Pittsburgh Medical Center- Shadyside Hospital</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>July 16, 2014</study_first_submitted>
  <study_first_submitted_qc>August 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 7, 2014</study_first_posted>
  <last_update_submitted>September 4, 2017</last_update_submitted>
  <last_update_submitted_qc>September 4, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Robert Ferris</investigator_full_name>
    <investigator_title>Professor of Otolaryngology</investigator_title>
  </responsible_party>
  <keyword>Squamous Cell Carcinoma</keyword>
  <keyword>Head &amp; Neck Cancer</keyword>
  <keyword>Vaccine</keyword>
  <keyword>Carcinoma</keyword>
  <keyword>Immunization</keyword>
  <keyword>Autologous Tumor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</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/NCT02211027
org study id: 13-160
nct id: NCT02211027
lead sponsor: 
collaborator: 
has dmc: Yes
Hypothesis The incidence of toxicity in patients receiving the tumor DNA-transfected
      fibroblast vaccine will be acceptably low and the immunologic response rate sufficiently high
      to warrant further study of this therapy

      The study of the vaccine will proceed in two stages after the method of Simon (102). In the
      first stage, 15 patients will be accrued and treated. If two or fewer objective immunologic
      responses occur, the study will be terminated. If 3 or more responses are observed, the study
      will proceed to the second stage, accruing an additional 22 patients. If the second stage is
      complete and a total of 9 or more immunologic responses are observed among the 37 patients
      treated, the treatment response rate for the vaccine will be considered high enough to
      warrant further study. Conversely, if the evaluation of the vaccine concludes at the first
      stage, or if 8 or fewer total immunologic responses occur after completing the second stage,
      the vaccine will not be considered for further study.
This is a single institution open-label phase Ib clinical trial designed to determine the
      safety of immunization of patients with resected Head and Neck Squamous Cell Carcinoma
      (HNSCC) with lethally irradiated semi-allogeneic human fibroblasts (MRC-5) transfected with
      DNA derived from the subject's own tumor and to measure the immune response to the autologous
      tumor vaccine.

      Briefly, the plan is to use a two-stage trial design and to initially enroll 15 patients with
      Head and Neck Squamous Cell Carcinoma (HNSCC). The patients will undergo surgical resection
      to provide complete removal of the primary lesion with negative gross and microscopic
      margins. A portion of the primary tumor specimen not necessary for the pathologic diagnosis
      will be obtained to serve as a source of DNA for preparing the vaccine. Each DNA-based
      vaccine will contain 1 x 10e7 DNA-transfected human allogeneic fibroblasts. The vaccine will
      be lethally irradiated before it is used for immunization. It will be administered
      intradermally in the Outpatient Clinic for a total of four vaccinations delivered at weekly
      intervals.

      Patients delayed-type hypersensitivity (DTH) responses will be tested but will not be an
      eligibility criterion. Immunologic response to the vaccine will be evaluated. If there is no
      evidence of toxicity, and >3 of the 15 initial patients show immunologic response, the second
      stage of the study will be opened for accrual of 22 patients.

      To determine patient's response to the DNA-based vaccines, the frequency of T cells reactive
      with recipient cells transfected with the autologous tumor DNA will be measured by ELISPOT
      for IFN-y and compared with the response to non-transfected fibroblasts prior to and after
      vaccination. All patients will be monitored for Immunologic response by assays include
      ELISPOT, flow cytometry for lymphocyte markers, Annexin V binding, TcR expression, caspase3
      activity and serum antibodies.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Immunization Safety
time frame: 2.5 years
description: Toxicity will be monitored continuously from the first vaccination through the 6 month post follow up study visit for each subject.
Patients will have a follow-up visit at 1 week after last vaccination (day 29, off treatment), at 1 month, 3 months and 6 months after last vaccination or after removal from study or until death, whichever occurs first. After the 6 month follow-up visit, subjects will be followed for survival only (no additional clinical trial site visits). Patients removed from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
All subjects should be enrolled within 2 years and follow up studies complete within 3 years.
measure: Immunologic Response Rate to the the tumor DNA-transfected fibroblast vaccine
time frame: 2.5 years
description: Immunologic evidence of a response to the DNA-based vaccine will depend on the results of ELISPOT assays performed at five to seven time points: pre-surgery, pre-vaccine (either at the day -28 or Day 1 prior to vaccination), on day 15, on day 29, 1 month, 3 months (if clinically indicated at 1 and 3 months) and at the 6 month post treatment follow-up appointment. A significant difference in the frequency of vaccine reactive or anti-tumor-reactive T cells between pre- and post-vaccine determinations will be considered as a positive immune response to the vaccine.
Additionally, immune competence and the presence/absence of immune suppression will be evaluated before and after vaccine administration. The ability of DNA-based vaccines to reverse or diminish demonstrated effects in signaling defects, lymphocyte apoptosis or proportions of T(reg) in the peripheral circulation will be measured but will not be used as a criterion for evaluation of the immune response.
measure: Immune competence
time frame: 2.5 years
description: Immune competence and the presence/absence of immune suppression will be evaluated before and after vaccine administration and at the 6 month follow-up visit. The ability of DNA-based vaccines to reverse or diminish demonstrated effects in signaling defects, lymphocyte apoptosis or proportions of T(reg) in the peripheral circulation will be measured but will not be used as a criterion for evaluation of the immune response.
arm group label: Vaccine
arm group type: Experimental
description: The vaccine is composed of lethally irradiated semi-allogenic human fibroblasts (MRC-5) transfected with genomic tumor DNA from the patients own tumor.
intervention type: Biological
intervention name: Semi-allogenic human fibroblast (MRC-5) transfected with DNA
description: Each vaccination consists of up to 1 x 10e7 (not less than 7 x 10e6) DNA-transfected irradiated fibroblasts. Each vaccination will be administered intradermally using a 1 mL syringe and a 25 gauge needle.The first immunization will be administered at least 12 weeks after surgery or completion of adjuvant chemotherapy and/or radiotherapy.Three additional vaccines will be administered once a week for a total of four vaccines.
Patients will have vaccinations administered at 4 different sites as follows:
Site #1: Right arm Site #2: Left arm Site #3: Right thigh Site #4: Left thigh. Approximately equal numbers of transfected fibroblasts will be administered at each site.
arm group label: Vaccine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Robert L Ferris, MD
role: Principal Investigator
affiliation: Professor of Otolaryngology, Eye & Ear Institute of the University of Pittsburgh Medical Center.
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Robert Ferris
investigator title: Professor of Otolaryngology
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Squamous Cell Carcinoma of Head and Neck