xml: <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/NCT06026657</url>
    </required_header>
    <id_info>
      <org_study_id>OSU-22237</org_study_id>
      <secondary_id>NCI-2023-06508</secondary_id>
      <nct_id>NCT06026657</nct_id>
    </id_info>
    <brief_title>Gemcitabine and Ex Vivo Expanded Allogenic Universal Donor, TGFβi Natural Killer (NK) Cells With or Without Naxitamab (Danyelza) for the Treatment of Patients With Metastatic, GD2 Expressing, HER2 Negative Breast Cancer</brief_title>
    <official_title>Phase 1b/2 Study of Naxitamab (Danyelza), Gemcitabine and Ex Vivo Expanded Allogenic Universal Donor, TGFβi Natural Killer (NK) Cells in Advanced GD2-expressing Breast Cancers (DiG NKs)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Margaret Gatti-Mays</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Ohio State University Comprehensive Cancer Center</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 phase Ib/II trial tests the safety, best dose and how well gemcitabine and ex vivo&#xD;
        expanded allogenic universal donor TGFBi NK cells with or without naxitamab work for the&#xD;
        treatment of patients with GD2 expressing, HER2 negative breast cancer that has spread from&#xD;
        where it first started (primary site) to other places in the body (metastatic). Gemcitabine&#xD;
        is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid (DNA) and may&#xD;
        kill cancer cells. TGFBi NK cells are manufactured cells that are a part of your natural&#xD;
        immunity. NK cells can recognize missing or incorrect proteins on tumor cells and then&#xD;
        eliminate these tumor cells and TGFBi NK cells are created to be able to better kill the&#xD;
        tumor cells. Naxitamab is a monoclonal antibody that targets GD2, which is a protein or sugar&#xD;
        present on tumor cells but not very commonly found on normal cells. This antibody helps draw&#xD;
        the attention of the immune system to the tumor cells that have GD2 to help attack the tumor&#xD;
        cells. Giving gemcitabine and TGFBi NK cells with or without naxitamab may kill more tumor&#xD;
        cells in patients with metastatic GD2 expressing, HER2 negative breast cancer.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        PRIMARY OBJECTIVES:&#xD;
  &#xD;
        I. To evaluate the safety of gemcitabine plus transforming growth factor beta imprinted&#xD;
        natural killer (TGFBi NKs) +/- naxitamab in metastatic breast cancer.&#xD;
  &#xD;
        II. To evaluate the objective response rate of gemcitabine plus TGFB NKs +/- naxitamab in&#xD;
        metastatic breast cancer.&#xD;
  &#xD;
        SECONDARY OBJECTIVES:&#xD;
  &#xD;
        I. To determine if TGFB NK cells are detectable in the peripheral blood 5 days following&#xD;
        infusion (C1D21).&#xD;
  &#xD;
        II. To determine if gemcitabine plus TGFB NKs +/- naxitamab improves median progression-free&#xD;
        survival (PFS) in metastatic breast cancer over historical controls for gemcitabine alone.&#xD;
  &#xD;
        EXPLORATORY OBJECTIVES:&#xD;
  &#xD;
        I. Peripheral blood mononuclear cells (PBMCs) Ia. Real-time blood immune profiling Ib.&#xD;
        Antigen specific immune responses II. Plasma/Serum IIa. TCR clonality IIb. Cytokines (IFNy,&#xD;
        IL-10, IL-12, IL-2, IL4, etc) and chemokines IIc. Antigen specific immune responses III.&#xD;
        Archival tissue IIIa. GD2 expression on tumor IIIb. Immunohistochemistry/multispectral&#xD;
        imaging IIIc. Tumor mutational burden&#xD;
  &#xD;
        OUTLINE: Patients are assigned to 1 of 4 arms.&#xD;
  &#xD;
        ARM I: Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1, 8, and 15&#xD;
        of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease&#xD;
        progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes&#xD;
        on day 16 of cycle 1.&#xD;
  &#xD;
        ARM II: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle.&#xD;
        Cycles repeat every 28 days for up to 1 year in the absence of disease progression or&#xD;
        unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18&#xD;
        of cycle 1.&#xD;
  &#xD;
        ARM III: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle&#xD;
        followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat&#xD;
        every 28 days for up to 1 year in the absence of disease progression or unacceptable&#xD;
        toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1.&#xD;
  &#xD;
        ARM IV: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle&#xD;
        followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat&#xD;
        every 28 days for up to 1 year in the absence of disease progression or unacceptable&#xD;
        toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1.&#xD;
  &#xD;
        Patients undergo computed tomography and blood sample collection and may undergo magnetic&#xD;
        resonance imaging (MRI) throughout the study.&#xD;
  &#xD;
        After completion of study treatment, patients are followed up within 30 days of stopping&#xD;
        treatment and every 3 months for 1 year.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">December 31, 2024</completion_date>
    <primary_completion_date type="Anticipated">December 31, 2024</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>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>Incidence of adverse events</measure>
      <time_frame>Up to 1 year after completion of study medication</time_frame>
      <description>Will be summarized descriptively with reporting of any dose limiting toxicities (DLTs) in these initial patients. In addition, to DLTs, serious adverse events (SAEs) and immune related adverse events of interest will be reported. Will be summarized descriptively and graphically, with reporting the outcome measures indicated along with two-tailed 95% confidence intervals (CIs). Number and frequency of patients experiencing each adverse event (AE) type and grade will tabulated, among patients evaluable for toxicity. The number (%) of patients experiencing at least one grade 3 to 5 AE will be reported with 95% CI.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Objective response rate</measure>
      <time_frame>Up to 1 year after completion of study medication</time_frame>
      <description>Will be estimated in each arm using two-sided 80% and 95% CI about the observed percentages of response (PR+CR).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Transforming growth factor beta imprinted natural killer (TGFBi NK) cell detection</measure>
      <time_frame>At day 5 following infusion</time_frame>
      <description>TGFBi NK cell persistence will be defined as the presence (detectable donor TGFBi NK cells) or the absence (no detectable donor TGFBi NK cells). Data will be described numerically as percentage of donor cells in blood and will be correlated to clinical outcomes.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Progression free survival</measure>
      <time_frame>From start of treatment to time of progression or death, whichever occurs first, up to 1 year after completion of study medication</time_frame>
      <description>Will be estimated using a Kaplan-Meier curve and the median PFS will be reported along with a 95% confidence interval, separately by arm, based on the patients who are enrolled in the evaluation of clinical response.</description>
    </secondary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">45</enrollment>
    <condition>Anatomic Stage IV Breast Cancer AJCC v8</condition>
    <condition>HER2-Negative Breast Carcinoma</condition>
    <arm_group>
      <arm_group_label>Arm I (Gemcitabine, TGFBi)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm II (Gemcitabine, TGFBi x2)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm III (Gemcitabine naxitamab, TGFBi)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm IV (Gemcitabine, naxitamab, TGFBi x2)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.</description>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Biospecimen Collection</intervention_name>
      <description>Undergo blood sample collection</description>
      <arm_group_label>Arm I (Gemcitabine, TGFBi)</arm_group_label>
      <arm_group_label>Arm II (Gemcitabine, TGFBi x2)</arm_group_label>
      <arm_group_label>Arm III (Gemcitabine naxitamab, TGFBi)</arm_group_label>
      <arm_group_label>Arm IV (Gemcitabine, naxitamab, TGFBi x2)</arm_group_label>
      <other_name>Biological Sample Collection</other_name>
      <other_name>Biospecimen Collected</other_name>
      <other_name>Specimen Collection</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Computed Tomography</intervention_name>
      <description>Undergo CT scan</description>
      <arm_group_label>Arm I (Gemcitabine, TGFBi)</arm_group_label>
      <arm_group_label>Arm II (Gemcitabine, TGFBi x2)</arm_group_label>
      <arm_group_label>Arm III (Gemcitabine naxitamab, TGFBi)</arm_group_label>
      <arm_group_label>Arm IV (Gemcitabine, naxitamab, TGFBi x2)</arm_group_label>
      <other_name>CAT</other_name>
      <other_name>CAT Scan</other_name>
      <other_name>Computed Axial Tomography</other_name>
      <other_name>Computerized Axial Tomography</other_name>
      <other_name>Computerized axial tomography (procedure)</other_name>
      <other_name>Computerized Tomography</other_name>
      <other_name>CT</other_name>
      <other_name>CT Scan</other_name>
      <other_name>tomography</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Gemcitabine</intervention_name>
      <description>Given IV</description>
      <arm_group_label>Arm I (Gemcitabine, TGFBi)</arm_group_label>
      <arm_group_label>Arm II (Gemcitabine, TGFBi x2)</arm_group_label>
      <arm_group_label>Arm III (Gemcitabine naxitamab, TGFBi)</arm_group_label>
      <arm_group_label>Arm IV (Gemcitabine, naxitamab, TGFBi x2)</arm_group_label>
      <other_name>dFdC</other_name>
      <other_name>dFdCyd</other_name>
      <other_name>Difluorodeoxycytidine</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Magnetic Resonance Imaging</intervention_name>
      <description>Undergo MRI</description>
      <arm_group_label>Arm I (Gemcitabine, TGFBi)</arm_group_label>
      <arm_group_label>Arm II (Gemcitabine, TGFBi x2)</arm_group_label>
      <arm_group_label>Arm III (Gemcitabine naxitamab, TGFBi)</arm_group_label>
      <arm_group_label>Arm IV (Gemcitabine, naxitamab, TGFBi x2)</arm_group_label>
      <other_name>Magnetic Resonance</other_name>
      <other_name>Magnetic resonance imaging (procedure)</other_name>
      <other_name>Magnetic Resonance Imaging Scan</other_name>
      <other_name>Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance</other_name>
      <other_name>MR</other_name>
      <other_name>MR Imaging</other_name>
      <other_name>MRI</other_name>
      <other_name>MRI Scan</other_name>
      <other_name>NMR Imaging</other_name>
      <other_name>NMRI</other_name>
      <other_name>Nuclear Magnetic Resonance Imaging</other_name>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Naxitamab</intervention_name>
      <description>Given IV</description>
      <arm_group_label>Arm III (Gemcitabine naxitamab, TGFBi)</arm_group_label>
      <arm_group_label>Arm IV (Gemcitabine, naxitamab, TGFBi x2)</arm_group_label>
      <other_name>Anti-Gd2 IGG3 Monoclonal Antibody 3f8 Humanized</other_name>
      <other_name>Danyelza</other_name>
      <other_name>Hu3F8</other_name>
      <other_name>Humanized Anti-GD2 Antibody 3F8</other_name>
      <other_name>Humanized Monoclonal Antibody Hu3f8-IGG1</other_name>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Universal Donor Expanded TGF-beta-imprinted NK Cells</intervention_name>
      <description>Given IV</description>
      <arm_group_label>Arm I (Gemcitabine, TGFBi)</arm_group_label>
      <arm_group_label>Arm II (Gemcitabine, TGFBi x2)</arm_group_label>
      <arm_group_label>Arm III (Gemcitabine naxitamab, TGFBi)</arm_group_label>
      <arm_group_label>Arm IV (Gemcitabine, naxitamab, TGFBi x2)</arm_group_label>
      <other_name>Allogeneic TGFBi Expanded NK Cells</other_name>
      <other_name>UD TGF-betai NK Cells</other_name>
      <other_name>Universal Donor TGF-beta Imprinted Expanded NK Cells</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients must have histologically or cytologically confirmed, HER2 negative metastatic&#xD;
               breast cancer that is historically GD2 expressing (e.g., triple negative breast&#xD;
               cancer, metaplastic breast cancer, high grade estrogen positive breast cancer) with&#xD;
               available archival tissue. Well differentiated neuroendocrine tumor (NETs) are not&#xD;
               eligible for this trial since GD2 expression is unknown. GD2 expression is not&#xD;
               required for eligibility but a primary tumor paraffin block is required at enrollment&#xD;
               for assessment of GD2 expression&#xD;
  &#xD;
            -  Patients must have measurable disease, per Response Evaluation Criteria in Solid&#xD;
               Tumors (RECIST 1.1) for the evaluation of measurable disease&#xD;
  &#xD;
            -  Patients must have received at least one prior treatment for metastatic disease and&#xD;
               progressed on treatment or been intolerant to treatment&#xD;
  &#xD;
            -  Female or male &gt;=18 years&#xD;
  &#xD;
            -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1&#xD;
  &#xD;
            -  Absolute neutrophil count &gt;= 1,500/mcL (&gt; 1.5 X 10^6/L)&#xD;
  &#xD;
            -  Platelets &gt;= 100,000/mcL&#xD;
  &#xD;
            -  Hemoglobin &gt;= 9 mg/dL (transfusion to obtain hemoglobin &gt;= 9 mg/dL within 24 hours&#xD;
               prior to dosing is allowed)&#xD;
  &#xD;
            -  Serum creatinine =&lt; 1.5 X upper limit of normal (ULN) or measured or calculated&#xD;
               creatinine clearance (CrCl) &gt;= 60 mL/min for participant with creatinine levels &gt; 1.5&#xD;
               X institutional upper limit of normal (ULN) (Glomerular filtration rate [GFR] can also&#xD;
               be used in place of creatinine or CrCl)&#xD;
  &#xD;
            -  Patients must have adequate hepatic function, defined as aspartate aminotransferase&#xD;
               (AST) and alanine aminotransferase (ALT) levels =&lt; 3 X ULN and total bilirubin &lt; 1.5 X&#xD;
               ULN, unless known diagnosis of Gilbert's syndrome, where bilirubin =&lt; 5 mg/dL will be&#xD;
               permitted. Gilbert's syndrome will be defined as elevated unconjugated bilirubin, with&#xD;
               conjugated (direct) bilirubin within the normal range and less than 20% of the total.&#xD;
               Total bilirubin will be permitted up to 5 mg/dL, if patients have historical readings&#xD;
               consistent with the definition of Gilbert's syndrome prior to entering study. Adequate&#xD;
               hepatic function for patients with known liver metastases is defined as AST and ALT&#xD;
               levels ≤ 5 X ULN&#xD;
  &#xD;
            -  The effects of the trial agents on the developing human fetus are unknown. However,&#xD;
               gemcitabine is known to have negative fetal effects. For this reason: Women of&#xD;
               childbearing potential must agree to use adequate contraception at study entry, for&#xD;
               the duration of study participation and for 7 months after the last dose of study&#xD;
               medication based upon estimated half-life or receptor occupancy. Adequate&#xD;
               contraception is defined as 2 highly effective methods of contraception (including a&#xD;
               physical barrier). Should a woman become pregnant or suspect she is pregnant while she&#xD;
               or her partner is participating in this study, she should inform her treating&#xD;
               physician immediately. Men should refrain from fathering a child using adequate&#xD;
               contraception or donating sperm during the study and for 6 months after the last dose&#xD;
               of study medications. Adequate contraception is defined as 2 highly effective methods&#xD;
               of contraception (including a physical barrier)&#xD;
  &#xD;
            -  Patients with well-controlled human immunodeficiency virus (HIV) infection are&#xD;
               eligible for trial as long as:&#xD;
  &#xD;
                 -  On an effective anti-retroviral therapy (ART) ˃ 4 weeks and with evidence of&#xD;
                    viral-suppression as defined as HIV viral load ˂ 400 copies/mL within the last 3&#xD;
                    months&#xD;
  &#xD;
                 -  CD4 &gt; 200 cells/µL within the last 3 months; and&#xD;
  &#xD;
                 -  No reported opportunistic infections within 6 months prior to enrollment, except&#xD;
                    for the following which will be allowed:&#xD;
  &#xD;
                      -  Esophageal candidiasis treated within last 6 months or currently improving&#xD;
                         with antifungal treatment.&#xD;
  &#xD;
                      -  Oral and/or genital herpes simplex virus (HSV) treated within last 6 months&#xD;
                         or currently improving with antiviral treatment.&#xD;
  &#xD;
                      -  Mycobacterium avium infection in last 6 months or that has been treated for&#xD;
                         at least 1 month&#xD;
  &#xD;
            -  Patients with evidence of chronic hepatitis B virus (HBV) infection are eligible for&#xD;
               trial as long as the HBV viral load is undetectable on suppressive therapy, if&#xD;
               indicated.&#xD;
  &#xD;
                 -  Patients with history of hepatitis C virus (HCV) infection must have been treated&#xD;
                    and cured. For patients with HCV infection who are currently on treatment, they&#xD;
                    are eligible if they have an undetectable or unquantifiable HCV ribonucleic acid&#xD;
                    (RNA) 12 weeks or longer after definitive treatment completion.&#xD;
  &#xD;
                 -  Patients must be able to understand and willing to sign a written informed&#xD;
                    consent document&#xD;
  &#xD;
            -  Any adverse events subjects have experienced from prior therapy must have resolved to&#xD;
               =&lt; grade 1 according to National Cancer Institute Common Terminology Criteria for&#xD;
               Adverse Events (NCI CTCAE) version 5&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients who within 3 weeks prior to study enrollment who have received chemotherapy,&#xD;
               investigational agents, or radiation&#xD;
  &#xD;
            -  Patients with active brain metastases or leptomeningeal metastases are excluded from&#xD;
               this clinical trial because they often develop progressive neurologic dysfunction that&#xD;
               would confound the evaluation of neurologic and other adverse events. However,&#xD;
               patients with treated brain metastases are eligible if there is no magnetic resonance&#xD;
               imaging (MRI) evidence of progression for 6 months after treatment is complete and&#xD;
               within 28 days prior to the first dose of trial drug. Patients requiring&#xD;
               immunosuppressive doses of systemic corticosteroids (&gt; 10mg/day prednisone equivalent)&#xD;
               for palliation are excluded&#xD;
  &#xD;
            -  Patients with a history of another invasive malignancy &lt; 3 years prior to enrollment&#xD;
               (patients with non-melanoma skin cancers, carcinoma in situ of the breast or cervix&#xD;
               are eligible)&#xD;
  &#xD;
            -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
               composition to agents used in study&#xD;
  &#xD;
            -  Uncontrolled intercurrent illness including, but not limited to, ongoing active&#xD;
               infection that requires systemic treatment with ongoing antibiotics (eligible if can&#xD;
               stop antibiotics on day of enrollment), unexplained fever (temperature &gt; 38.1˚celcius&#xD;
               [C]) within 7 days of initial treatment, unstable angina pectoris, cardiac arrhythmia,&#xD;
               or psychiatric illness/social situation that in the opinion of the primary&#xD;
               investigator would prohibit the patient from complying with study requirements&#xD;
  &#xD;
            -  Patients with bone metastases who have initiated denosumab or a bisphosphonate therapy&#xD;
               within 28 days prior to or after cycle 1 day 1 due to the potential for flu-like&#xD;
               symptoms and mild cytokine release syndrome with the initial dose. However,&#xD;
               continuation of prior therapy is allowed&#xD;
  &#xD;
            -  Patients should have no evidence of being immunocompromised as listed below:&#xD;
  &#xD;
                 -  Active, known or suspected autoimmune disease. Patients are permitted to enroll&#xD;
                    if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to&#xD;
                    an autoimmune condition only requiring hormone replacement, psoriasis not&#xD;
                    requiring systemic treatment or conditions not expected to recur in the absence&#xD;
                    of an external trigger in the opinion of the primary investigator&#xD;
  &#xD;
                 -  Altered immune function that in the judgement of the PI that may affect a&#xD;
                    patient's ability to adequately engage the immune system and respond to the&#xD;
                    immunotherapy agents being administered, including but not limited to:&#xD;
                    inflammatory bowel disease; active infectious enteritis; eosinophilic enteritis;&#xD;
                    lupus erythematous; ankylosing spondylitis; scleroderma; multiple sclerosis.&#xD;
                    These criteria do not include all disease with an immune-related component but&#xD;
                    are not autoimmune in nature or have a primary alteration in the general immune&#xD;
                    function that may interfere with the vaccine mechanism of action, for example&#xD;
                    celiac disease&#xD;
  &#xD;
                 -  Immunosuppressive therapy post-organ transplant&#xD;
  &#xD;
                 -  Concurrent use of chronic use of systemic steroids, except for physiologic doses&#xD;
                    of systemic steroids for replacement, defined as 10mg of prednisone per day or&#xD;
                    equivalent, or local (topical, nasal, ophthalmic or inhaled) steroid use or prior&#xD;
                    concomitant use with chemotherapy. Systemic steroids must have been discontinued&#xD;
                    &gt;2 weeks prior to trial start. Prior use of corticosteroids in short-term schemes&#xD;
                    (duration shorter than 3 days) for indications such as prophylaxis of reactions&#xD;
                    to intravenous contrast for imaging studies or chemotherapy-related adverse&#xD;
                    events (AEs) are not considered part of this exclusion. Prior use of&#xD;
                    corticosteroids for brain metastasis ending at least 14 days prior to enrollment&#xD;
                    is not considered part of this exclusion criteria&#xD;
  &#xD;
            -  Pregnant and breastfeeding women are excluded from this study because of the potential&#xD;
               for teratogenic or abortifacient effects with all of the agents involved in this&#xD;
               trial. Females of childbearing potential who are pregnant, breast feeding, intend to&#xD;
               become pregnant, or are not using adequate contraceptive methods or males who are not&#xD;
               using adequate contraceptive methods. Women of childbearing potential must agree to&#xD;
               use two methods of adequate contraception at study entry be used for the duration of&#xD;
               study participation and for at least 7 months for women and 6 months for men after the&#xD;
               final dose of any study-related medications&#xD;
  &#xD;
            -  Clinically significant cardiomyopathy, coronary disease, myocardial infarction,&#xD;
               chronic heart failure (CHF) (New York Heart Association class III or IV or&#xD;
               hospitalization for CHF), ejection fraction &lt; 50% or cerebrovascular accident within 6&#xD;
               months prior to enrollment&#xD;
  &#xD;
            -  Patients with a history of myocarditis are excluded due to the potential of&#xD;
               myocarditis with anti-PD-L1 antibodies or other immunotherapies&#xD;
  &#xD;
            -  Patients who have received any live vaccines within 30 days prior to enrollment&#xD;
               (inactivated vaccines including COVID vaccines are allowed)&#xD;
  &#xD;
            -  Any other condition, which would, in the opinion of the principal investigator the&#xD;
               subject is a poor candidate for the clinical trial or would jeopardize the subject or&#xD;
               the integrity of the data obtained&#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>Margaret E Gatti-Mays, MD MPH</last_name>
      <role>Principal Investigator</role>
      <affiliation>Ohio State University Comprehensive Cancer Center</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>The Ohio State University Comprehensive Cancer Center</last_name>
      <phone>800-293-5066</phone>
      <email>OSUCCCClinicaltrials@osumc.edu</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Amanda Kabetso</last_name>
      <phone>614-257-2400</phone>
      <email>amanda.kabetso@osumc.edu</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Ohio State University Comprehensive Cancer Center</name>
        <address>
          <city>Columbus</city>
          <state>Ohio</state>
          <zip>43210</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Margaret E. Gatti-Mays</last_name>
        <phone>614-293-0066</phone>
      </contact>
      <investigator>
        <last_name>Margaret E. Gatti-Mays</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <link>
      <url>http://cancer.osu.edu</url>
      <description>The Jamesline</description>
    </link>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 30, 2023</study_first_submitted>
    <study_first_submitted_qc>August 30, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 7, 2023</study_first_posted>
    <last_update_submitted>August 30, 2023</last_update_submitted>
    <last_update_submitted_qc>August 30, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>Ohio State University Comprehensive Cancer Center</investigator_affiliation>
      <investigator_full_name>Margaret Gatti-Mays</investigator_full_name>
      <investigator_title>Principal Investigator</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Breast Neoplasms</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Gemcitabine</mesh_term>
      <mesh_term>Antineoplastic Agents, Immunological</mesh_term>
      <mesh_term>Antibodies</mesh_term>
      <mesh_term>Immunoglobulins</mesh_term>
      <mesh_term>Antibodies, Monoclonal</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06026657
  org study id: OSU-22237
  secondary id: NCI-2023-06508
  nct id: NCT06026657
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  This phase Ib/II trial tests the safety, best dose and how well gemcitabine and ex vivo
        expanded allogenic universal donor TGFBi NK cells with or without naxitamab work for the
        treatment of patients with GD2 expressing, HER2 negative breast cancer that has spread from
        where it first started (primary site) to other places in the body (metastatic). Gemcitabine
        is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid (DNA) and may
        kill cancer cells. TGFBi NK cells are manufactured cells that are a part of your natural
        immunity. NK cells can recognize missing or incorrect proteins on tumor cells and then
        eliminate these tumor cells and TGFBi NK cells are created to be able to better kill the
        tumor cells. Naxitamab is a monoclonal antibody that targets GD2, which is a protein or sugar
        present on tumor cells but not very commonly found on normal cells. This antibody helps draw
        the attention of the immune system to the tumor cells that have GD2 to help attack the tumor
        cells. Giving gemcitabine and TGFBi NK cells with or without naxitamab may kill more tumor
        cells in patients with metastatic GD2 expressing, HER2 negative breast cancer.
  PRIMARY OBJECTIVES:
  
        I. To evaluate the safety of gemcitabine plus transforming growth factor beta imprinted
        natural killer (TGFBi NKs) +/- naxitamab in metastatic breast cancer.
  
        II. To evaluate the objective response rate of gemcitabine plus TGFB NKs +/- naxitamab in
        metastatic breast cancer.
  
        SECONDARY OBJECTIVES:
  
        I. To determine if TGFB NK cells are detectable in the peripheral blood 5 days following
        infusion (C1D21).
  
        II. To determine if gemcitabine plus TGFB NKs +/- naxitamab improves median progression-free
        survival (PFS) in metastatic breast cancer over historical controls for gemcitabine alone.
  
        EXPLORATORY OBJECTIVES:
  
        I. Peripheral blood mononuclear cells (PBMCs) Ia. Real-time blood immune profiling Ib.
        Antigen specific immune responses II. Plasma/Serum IIa. TCR clonality IIb. Cytokines (IFNy,
        IL-10, IL-12, IL-2, IL4, etc) and chemokines IIc. Antigen specific immune responses III.
        Archival tissue IIIa. GD2 expression on tumor IIIb. Immunohistochemistry/multispectral
        imaging IIIc. Tumor mutational burden
  
        OUTLINE: Patients are assigned to 1 of 4 arms.
  
        ARM I: Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1, 8, and 15
        of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease
        progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes
        on day 16 of cycle 1.
  
        ARM II: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle.
        Cycles repeat every 28 days for up to 1 year in the absence of disease progression or
        unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18
        of cycle 1.
  
        ARM III: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle
        followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat
        every 28 days for up to 1 year in the absence of disease progression or unacceptable
        toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1.
  
        ARM IV: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle
        followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat
        every 28 days for up to 1 year in the absence of disease progression or unacceptable
        toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1.
  
        Patients undergo computed tomography and blood sample collection and may undergo magnetic
        resonance imaging (MRI) throughout the study.
  
        After completion of study treatment, patients are followed up within 30 days of stopping
        treatment and every 3 months for 1 year.
  allocation: Non-Randomized
  intervention model: Sequential Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Incidence of adverse events
  time frame: Up to 1 year after completion of study medication
  description: Will be summarized descriptively with reporting of any dose limiting toxicities (DLTs) in these initial patients. In addition, to DLTs, serious adverse events (SAEs) and immune related adverse events of interest will be reported. Will be summarized descriptively and graphically, with reporting the outcome measures indicated along with two-tailed 95% confidence intervals (CIs). Number and frequency of patients experiencing each adverse event (AE) type and grade will tabulated, among patients evaluable for toxicity. The number (%) of patients experiencing at least one grade 3 to 5 AE will be reported with 95% CI.
  measure: Objective response rate
  time frame: Up to 1 year after completion of study medication
  description: Will be estimated in each arm using two-sided 80% and 95% CI about the observed percentages of response (PR+CR).
  measure: Transforming growth factor beta imprinted natural killer (TGFBi NK) cell detection
  time frame: At day 5 following infusion
  description: TGFBi NK cell persistence will be defined as the presence (detectable donor TGFBi NK cells) or the absence (no detectable donor TGFBi NK cells). Data will be described numerically as percentage of donor cells in blood and will be correlated to clinical outcomes.
  measure: Progression free survival
  time frame: From start of treatment to time of progression or death, whichever occurs first, up to 1 year after completion of study medication
  description: Will be estimated using a Kaplan-Meier curve and the median PFS will be reported along with a 95% confidence interval, separately by arm, based on the patients who are enrolled in the evaluation of clinical response.
  arm group label: Arm I (Gemcitabine, TGFBi)
  arm group type: Experimental
  description: Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.
  arm group label: Arm II (Gemcitabine, TGFBi x2)
  arm group type: Experimental
  description: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.
  arm group label: Arm III (Gemcitabine naxitamab, TGFBi)
  arm group type: Experimental
  description: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.
  arm group label: Arm IV (Gemcitabine, naxitamab, TGFBi x2)
  arm group type: Experimental
  description: Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.
  intervention type: Procedure
  intervention name: Biospecimen Collection
  description: Undergo blood sample collection
  arm group label: Arm I (Gemcitabine, TGFBi)
  arm group label: Arm II (Gemcitabine, TGFBi x2)
  arm group label: Arm III (Gemcitabine naxitamab, TGFBi)
  arm group label: Arm IV (Gemcitabine, naxitamab, TGFBi x2)
  other name: Biological Sample Collection
  other name: Biospecimen Collected
  other name: Specimen Collection
  intervention type: Procedure
  intervention name: Computed Tomography
  description: Undergo CT scan
  arm group label: Arm I (Gemcitabine, TGFBi)
  arm group label: Arm II (Gemcitabine, TGFBi x2)
  arm group label: Arm III (Gemcitabine naxitamab, TGFBi)
  arm group label: Arm IV (Gemcitabine, naxitamab, TGFBi x2)
  other name: CAT
  other name: CAT Scan
  other name: Computed Axial Tomography
  other name: Computerized Axial Tomography
  other name: Computerized axial tomography (procedure)
  other name: Computerized Tomography
  other name: CT
  other name: CT Scan
  other name: tomography
  intervention type: Drug
  intervention name: Gemcitabine
  description: Given IV
  arm group label: Arm I (Gemcitabine, TGFBi)
  arm group label: Arm II (Gemcitabine, TGFBi x2)
  arm group label: Arm III (Gemcitabine naxitamab, TGFBi)
  arm group label: Arm IV (Gemcitabine, naxitamab, TGFBi x2)
  other name: dFdC
  other name: dFdCyd
  other name: Difluorodeoxycytidine
  intervention type: Procedure
  intervention name: Magnetic Resonance Imaging
  description: Undergo MRI
  arm group label: Arm I (Gemcitabine, TGFBi)
  arm group label: Arm II (Gemcitabine, TGFBi x2)
  arm group label: Arm III (Gemcitabine naxitamab, TGFBi)
  arm group label: Arm IV (Gemcitabine, naxitamab, TGFBi x2)
  other name: Magnetic Resonance
  other name: Magnetic resonance imaging (procedure)
  other name: Magnetic Resonance Imaging Scan
  other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  other name: MR
  other name: MR Imaging
  other name: MRI
  other name: MRI Scan
  other name: NMR Imaging
  other name: NMRI
  other name: Nuclear Magnetic Resonance Imaging
  intervention type: Biological
  intervention name: Naxitamab
  description: Given IV
  arm group label: Arm III (Gemcitabine naxitamab, TGFBi)
  arm group label: Arm IV (Gemcitabine, naxitamab, TGFBi x2)
  other name: Anti-Gd2 IGG3 Monoclonal Antibody 3f8 Humanized
  other name: Danyelza
  other name: Hu3F8
  other name: Humanized Anti-GD2 Antibody 3F8
  other name: Humanized Monoclonal Antibody Hu3f8-IGG1
  intervention type: Biological
  intervention name: Universal Donor Expanded TGF-beta-imprinted NK Cells
  description: Given IV
  arm group label: Arm I (Gemcitabine, TGFBi)
  arm group label: Arm II (Gemcitabine, TGFBi x2)
  arm group label: Arm III (Gemcitabine naxitamab, TGFBi)
  arm group label: Arm IV (Gemcitabine, naxitamab, TGFBi x2)
  other name: Allogeneic TGFBi Expanded NK Cells
  other name: UD TGF-betai NK Cells
  other name: Universal Donor TGF-beta Imprinted Expanded NK Cells
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Margaret E Gatti-Mays, MD MPH
  role: Principal Investigator
  affiliation: Ohio State University Comprehensive Cancer Center
  last name: The Ohio State University Comprehensive Cancer Center
  phone: 800-293-5066
  email: OSUCCCClinicaltrials@osumc.edu
  last name: Amanda Kabetso
  phone: 614-257-2400
  email: amanda.kabetso@osumc.edu
  facility: 
  contact: 
  investigator: 
  country: United States
  url: http://cancer.osu.edu
  description: The Jamesline
  responsible party type: Sponsor-Investigator
  investigator affiliation: Ohio State University Comprehensive Cancer Center
  investigator full name: Margaret Gatti-Mays
  investigator title: Principal Investigator
  mesh term: Breast Neoplasms
  mesh term: Gemcitabine
  mesh term: Antineoplastic Agents, Immunological
  mesh term: Antibodies
  mesh term: Immunoglobulins
  mesh term: Antibodies, Monoclonal
  sharing ipd: No