<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/NCT03269526</url>
  </required_header>
  <id_info>
    <org_study_id>19236</org_study_id>
    <nct_id>NCT03269526</nct_id>
  </id_info>
  <brief_title>BATs Treatment for Pancreatic Cancer, Phase Ib/II</brief_title>
  <official_title>Phase Ib/II Treatment of Advanced Pancreatic Cancer With Anti-CD3 x Anti-EGFR-Bispecific Antibody Armed Activated T-Cells (BATs)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Virginia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Virginia</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This protocol will confirm toxicities and estimate the clinical efficacy of combining&#xD;
      anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed activated T cells (EGFR BATs) given&#xD;
      to patients with locally advanced or metastatic pancreatic cancer who have received at least&#xD;
      one dose of first line chemotherapy and may have responding, stable or progressive disease.&#xD;
      Phase Ib will confirm a safe dose of 8 infusions, given twice weekly, of EGFR-BATs in 3 to 6&#xD;
      subjects. The phase II portion of the trial will test the clinical efficacy of this dose in&#xD;
      22 patients (including those in Phase Ib).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Once subjects are determined eligible, white blood cells (lymphocytes) are collected via&#xD;
      leukapheresis procedure at approximately 3 to 4 weeks prior to first EGFR-BATs infusion. The&#xD;
      white blood cells, specifically T cells, are then mixed with two proteins - OKT3 and IL-2&#xD;
      which activates the cells to multiply. After approximately 14 days in culture, the activated&#xD;
      T cells are coated with the OKT3 and cetuximab to produce bispecific antibody armed T cells&#xD;
      (BATs). Cells are then frozen and stored until scheduled to be infused.&#xD;
&#xD;
      Within one to two weeks prior to infusion of the study treatment, subjects will receive one&#xD;
      dose of chemotherapy. The choice of chemotherapy agent(s) is at the discretion of the&#xD;
      treating physician.&#xD;
&#xD;
      At approximately 4 weeks following leukapheresis procedure, twice weekly or weekly infusions&#xD;
      of the BATs cells will take place (twice weekly for participants enrolled before DATE and&#xD;
      weekly for participants enrolled after DATE). A total of eight twice weekly infusions or four&#xD;
      weekly infusions will be given over a four week period. Please note that the weekly dose for&#xD;
      both groups of participants is the same; participants that received twice weekly dosing&#xD;
      received half of the weekly dose at each infusion.&#xD;
&#xD;
      Follow-up appointment schedule will include clinic visits at 1 to 2 weeks, 4 to 5 weeks, 2&#xD;
      months, 4 months and 6 months following the last infusion of BATs cells.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 28, 2017</start_date>
  <completion_date type="Anticipated">June 1, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 2025</primary_completion_date>
  <phase>Phase 1/Phase 2</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>
    <intervention_model_description>Standard of care chemotherapy followed by Anti-CD3 x anti-EGFR-Bispecific Antibody Armed Activated T-cells</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>From the beginning of treatment (bridging chemotherapy) until no sooner than 30 days following the last study treatment</time_frame>
    <description>Safety will be assessed by incidence and severity of adverse events, changes in laboratory findings, physical examinations, vital signs, and the number of dose limiting toxicities and other discontinuations due to adverse events.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Until subject's death or study closure (whichever occurs first) for an average of 36 months from study treatment completion</time_frame>
    <description>An improvement in median overall survival (OS), defined as an increase from historical data of 8.7 months to 18.0 months.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cellular or humoral anti-pancreatic cancer responses</measure>
    <time_frame>Every 2-6 months after the last EGFR BATs infusion for as long as the response lasts -- an average of 4 months</time_frame>
    <description>These will be measured in peripheral blood mononuclear cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Efficacy</measure>
    <time_frame>Imaging will be performed prior to treatment, 2 months after the last BATs infusion, then according to standard of care for an average of 12 months</time_frame>
    <description>Progression-free survival, measured by immune-related response criteria (irRC)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Examine tumor tissue for immune system cells, cytokines and proteins to estimate whether the type and number of immune cells correlates with clinical responses</measure>
    <time_frame>Tumor paraffin blocks from tissue collected prior to treatment will be batched and analyzed within 1 year of completion of study accrual</time_frame>
    <description>These immune system cells, cytokines and proteins include CD3, CD4, CD8, PD1/PDL1, monocytes subpopulations, MDSCs, and cytoplasmic IFN-y, tumor infiltrating lymphocytes, and IL-10. This will be measured using immunohistochemical staining to quantitate type and number of immune system cells, cytokines, and proteins to estimate whether the type and number correlate with clinical responses.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Locally Advanced Pancreatic Adenocarcinoma</condition>
  <condition>Metastatic Pancreatic Adenocarcinoma</condition>
  <arm_group>
    <arm_group_label>EGFR BATs after standard of care chemo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will undergo apheresis to collect peripheral blood mononuclear cells. Cells will be cultured for up to 2 weeks before activated T-cells will be harvested, armed with EGFR Biarmed activated T-cells, washed to remove unbound EGFRBi, and cryopreserved. Subjects will then receive one dose of standard of care chemotherapy prior to receiving EGFR BATs.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EGFR BATs after standard of care chemo</intervention_name>
    <description>Subjects will receive one dose of standard of care chemotherapy prior to twice weekly or weekly infusions of EGFR BATs for 4 weeks.</description>
    <arm_group_label>EGFR BATs after standard of care chemo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histological or cytological proof of pancreatic adenocarcinoma. Must have locally&#xD;
             advanced or metastatic pancreatic cancer and received at least one dose of&#xD;
             chemotherapy (any treatment line) and may have responding, stable or progressive&#xD;
             disease&#xD;
&#xD;
          2. Expected survival ≥ 3 months&#xD;
&#xD;
          3. ECOG Performance Status 0 or 1&#xD;
&#xD;
          4. Left Ventricular Ejection Fraction (LVEF) ≥ 45% at rest (MUGA or Echo)&#xD;
&#xD;
          5. Age ≥ 18 years at the time of consent (Written informed consent and HIPAA&#xD;
             authorization for release of personal health information)&#xD;
&#xD;
          6. Females of childbearing potential, and males, must be willing to use an effective&#xD;
             method of contraception&#xD;
&#xD;
          7. Females of childbearing potential must have a negative pregnancy test within 10 days&#xD;
             prior to &quot;on study&quot; status. If a urine or serum test is positive or cannot be&#xD;
             confirmed as negative, the other (urine or serum pregnancy test, whichever was not&#xD;
             performed first) will be required.&#xD;
&#xD;
          8. Demonstrate adequate hepatic, renal, and bone marrow function as defined below; all&#xD;
             hematological, renal, and hepatic screening labs should be performed within 10 days&#xD;
             prior to &quot;on study&quot; status (alpha gal testing must be within the regular screening&#xD;
             period).&#xD;
&#xD;
               -  Absolute lymphocyte count ≥ 400/mm3&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1,000/mm3&#xD;
&#xD;
               -  Platelets ≥ 75,000/mm3&#xD;
&#xD;
               -  Hemoglobin ≥ 8 g/dL&#xD;
&#xD;
               -  Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be&#xD;
                  used in place of creatinine or CrCl) &lt; 2.0 mg/dl OR ≥50 ml/mm&#xD;
&#xD;
               -  Serum total bilirubin ≤ 2 mg/dl (biliary stent is allowed)&#xD;
&#xD;
               -  AST (SGOT) and ALT (SGPT) &lt; 5.0 times normal&#xD;
&#xD;
               -  Alpha 1,3 Galactose IgE (&quot;alpha gal&quot;) &lt; 0.35 IU/ml or &quot;negative&quot;&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known hypersensitivity to cetuximab or other EGFR antibody&#xD;
&#xD;
          2. Treatment with any investigational agent within 14 days prior to first study&#xD;
             intervention (apheresis) for protocol therapy&#xD;
&#xD;
          3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy&#xD;
             or any other form of immunosuppressive therapy within 7 days prior to first study&#xD;
             intervention (apheresis). Replacement therapy (eg., thyroxine, insulin, or physiologic&#xD;
             corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is&#xD;
             not considered a form of systemic treatment.&#xD;
&#xD;
          4. Serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy&#xD;
             or significant traumatic injury within 28 days prior to &quot;on-study&quot; status&#xD;
&#xD;
          5. Active liver disease such as cirrhosis, chronic active hepatitis or chronic persistent&#xD;
             hepatitis&#xD;
&#xD;
          6. Is HIV positive or has evidence of active Hepatitis C virus or active Hepatitis B&#xD;
             virus. If initial Hepatitis C test shows a positive result, the patient should have a&#xD;
             Hepatitis viral load test to confirm. If initial HIV or Hepatitis B virus testing&#xD;
             shows a positive result, no further testing will be done.&#xD;
&#xD;
          7. Active bleeding or a pathological condition that is associated with a high risk of&#xD;
             bleeding (therapeutic anticoagulation is allowed)&#xD;
&#xD;
          8. Has an active infection requiring systemic therapy&#xD;
&#xD;
          9. A serious uncontrolled medical disorder that in the opinion of the Investigator may be&#xD;
             jeopardized by the treatment with protocol therapy&#xD;
&#xD;
         10. Has a known history of active TB (Bacillus Tuberculosis)&#xD;
&#xD;
         11. Has had prior chemotherapy, radiation, hormonal, monoclonal antibody (mAb) or targeted&#xD;
             small molecule therapy, within 2 weeks prior to the first study procedure (apheresis).&#xD;
             Subjects who have not recovered to &lt;Grade 3 from an adverse event due to a previously&#xD;
             administered agent are not eligible.&#xD;
&#xD;
         12. Has received a live vaccine within 30 days of first study procedure (apheresis).&#xD;
&#xD;
         13. History of a recent myocardial infarction (within one year), a past myocardial&#xD;
             infarction (more than one year ago) along with current coronary symptoms requiring&#xD;
             medications.&#xD;
&#xD;
         14. Has history of another malignancy within the past 5 years. Exceptions include&#xD;
&#xD;
               -  basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has&#xD;
                  undergone potentially curative therapy&#xD;
&#xD;
               -  in situ cervical cancer.&#xD;
&#xD;
         15. Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment.&#xD;
&#xD;
         16. Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating investigator.&#xD;
&#xD;
         17. Females must not be breastfeeding&#xD;
&#xD;
         18. Pt may be excluded if, in the opinion of the PI and investigator team, the pt is not&#xD;
             capable of being compliant&#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>Tri Le, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Virginia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Lum LG, Thakur A, Al-Kadhimi Z, Colvin GA, Cummings FJ, Legare RD, Dizon DS, Kouttab N, Maizel A, Colaiace W, Liu Q, Rathore R. Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. Clin Cancer Res. 2015 May 15;21(10):2305-14. doi: 10.1158/1078-0432.CCR-14-2280. Epub 2015 Feb 16.</citation>
    <PMID>25688159</PMID>
  </reference>
  <reference>
    <citation>Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum LG. Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. Prostate Cancer. 2015;2015:285193. doi: 10.1155/2015/285193. Epub 2015 Feb 23.</citation>
    <PMID>25802762</PMID>
  </reference>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>August 11, 2017</study_first_submitted>
  <study_first_submitted_qc>August 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 31, 2017</study_first_posted>
  <last_update_submitted>July 21, 2023</last_update_submitted>
  <last_update_submitted_qc>July 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Virginia</investigator_affiliation>
    <investigator_full_name>Tri Minh Le, MD</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Pancreatic Cancer</keyword>
  <keyword>Pancreatic Adenocarcinoma</keyword>
  <keyword>Adoptive cell therapy</keyword>
  <keyword>Armed activated T-cells</keyword>
  <keyword>Bispecific antibody</keyword>
  <keyword>Immunotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenocarcinoma</mesh_term>
    <mesh_term>Pancreatic Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03269526
org study id: 19236
nct id: NCT03269526
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This protocol will confirm toxicities and estimate the clinical efficacy of combining
      anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed activated T cells (EGFR BATs) given
      to patients with locally advanced or metastatic pancreatic cancer who have received at least
      one dose of first line chemotherapy and may have responding, stable or progressive disease.
      Phase Ib will confirm a safe dose of 8 infusions, given twice weekly, of EGFR-BATs in 3 to 6
      subjects. The phase II portion of the trial will test the clinical efficacy of this dose in
      22 patients (including those in Phase Ib).
Once subjects are determined eligible, white blood cells (lymphocytes) are collected via
      leukapheresis procedure at approximately 3 to 4 weeks prior to first EGFR-BATs infusion. The
      white blood cells, specifically T cells, are then mixed with two proteins - OKT3 and IL-2
      which activates the cells to multiply. After approximately 14 days in culture, the activated
      T cells are coated with the OKT3 and cetuximab to produce bispecific antibody armed T cells
      (BATs). Cells are then frozen and stored until scheduled to be infused.

      Within one to two weeks prior to infusion of the study treatment, subjects will receive one
      dose of chemotherapy. The choice of chemotherapy agent(s) is at the discretion of the
      treating physician.

      At approximately 4 weeks following leukapheresis procedure, twice weekly or weekly infusions
      of the BATs cells will take place (twice weekly for participants enrolled before DATE and
      weekly for participants enrolled after DATE). A total of eight twice weekly infusions or four
      weekly infusions will be given over a four week period. Please note that the weekly dose for
      both groups of participants is the same; participants that received twice weekly dosing
      received half of the weekly dose at each infusion.

      Follow-up appointment schedule will include clinic visits at 1 to 2 weeks, 4 to 5 weeks, 2
      months, 4 months and 6 months following the last infusion of BATs cells.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Standard of care chemotherapy followed by Anti-CD3 x anti-EGFR-Bispecific Antibody Armed Activated T-cells
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of adverse events
time frame: From the beginning of treatment (bridging chemotherapy) until no sooner than 30 days following the last study treatment
description: Safety will be assessed by incidence and severity of adverse events, changes in laboratory findings, physical examinations, vital signs, and the number of dose limiting toxicities and other discontinuations due to adverse events.
measure: Overall survival
time frame: Until subject's death or study closure (whichever occurs first) for an average of 36 months from study treatment completion
description: An improvement in median overall survival (OS), defined as an increase from historical data of 8.7 months to 18.0 months.
measure: Cellular or humoral anti-pancreatic cancer responses
time frame: Every 2-6 months after the last EGFR BATs infusion for as long as the response lasts -- an average of 4 months
description: These will be measured in peripheral blood mononuclear cells
measure: Clinical Efficacy
time frame: Imaging will be performed prior to treatment, 2 months after the last BATs infusion, then according to standard of care for an average of 12 months
description: Progression-free survival, measured by immune-related response criteria (irRC)
measure: Examine tumor tissue for immune system cells, cytokines and proteins to estimate whether the type and number of immune cells correlates with clinical responses
time frame: Tumor paraffin blocks from tissue collected prior to treatment will be batched and analyzed within 1 year of completion of study accrual
description: These immune system cells, cytokines and proteins include CD3, CD4, CD8, PD1/PDL1, monocytes subpopulations, MDSCs, and cytoplasmic IFN-y, tumor infiltrating lymphocytes, and IL-10. This will be measured using immunohistochemical staining to quantitate type and number of immune system cells, cytokines, and proteins to estimate whether the type and number correlate with clinical responses.
arm group label: EGFR BATs after standard of care chemo
arm group type: Experimental
description: Subjects will undergo apheresis to collect peripheral blood mononuclear cells. Cells will be cultured for up to 2 weeks before activated T-cells will be harvested, armed with EGFR Biarmed activated T-cells, washed to remove unbound EGFRBi, and cryopreserved. Subjects will then receive one dose of standard of care chemotherapy prior to receiving EGFR BATs.
intervention type: Drug
intervention name: EGFR BATs after standard of care chemo
description: Subjects will receive one dose of standard of care chemotherapy prior to twice weekly or weekly infusions of EGFR BATs for 4 weeks.
arm group label: EGFR BATs after standard of care chemo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Tri Le, MD
role: Principal Investigator
affiliation: University of Virginia
facility: 
country: United States
citation: Lum LG, Thakur A, Al-Kadhimi Z, Colvin GA, Cummings FJ, Legare RD, Dizon DS, Kouttab N, Maizel A, Colaiace W, Liu Q, Rathore R. Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. Clin Cancer Res. 2015 May 15;21(10):2305-14. doi: 10.1158/1078-0432.CCR-14-2280. Epub 2015 Feb 16.
PMID: 25688159
citation: Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum LG. Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. Prostate Cancer. 2015;2015:285193. doi: 10.1155/2015/285193. Epub 2015 Feb 23.
PMID: 25802762
responsible party type: Principal Investigator
investigator affiliation: University of Virginia
investigator full name: Tri Minh Le, MD
investigator title: Assistant Professor
mesh term: Adenocarcinoma
mesh term: Pancreatic Neoplasms
sharing ipd: No