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/NCT05993611</url>
    </required_header>
    <id_info>
      <org_study_id>22375</org_study_id>
      <secondary_id>NCI-2023-04067</secondary_id>
      <secondary_id>22375</secondary_id>
      <secondary_id>P30CA033572</secondary_id>
      <nct_id>NCT05993611</nct_id>
    </id_info>
    <brief_title>Allogeneic CD6 Chimeric Antigen Receptor T Regulatory Cells (CD6-CAR Tregs) for the Treatment of Patients With Chronic Graft Versus Host Disease After Allogeneic Hematopoietic Cell Transplantation</brief_title>
    <official_title>A First-in-Human Study to Evaluate the Safety, Feasibility and Tolerability of Allogeneic CD6 Chimeric Antigen Receptor T Regulatory Cells (CD6-CAR Tregs) in Patients With Chronic Graft-Versus-Host Disease (cGVHD) After Allogeneic Hematopoietic Cell Transplantation (alloHCT)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>City of Hope Medical Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>National Cancer Institute (NCI)</agency>
        <agency_class>NIH</agency_class>
      </collaborator>
    </sponsors>
    <source>City of Hope Medical 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 I trial tests the safety, side effects, and best dose of allogeneic CD6 chimeric&#xD;
        antigen receptor T regulatory cells (CD6-CAR Tregs) in treating patients who have chronic&#xD;
        graft versus host disease (cGVHD) after an allogeneic hematopoietic cell transplantation&#xD;
        (HCT). An allogeneic HCT is an established treatment for benign or malignant blood and marrow&#xD;
        conditions where healthy stem cells from a donor are infused into a patient to help the&#xD;
        patient's bone marrow make more healthy cells and platelets. GVHD is a systemic disorder that&#xD;
        occurs when the graft's immune cells recognize the host as foreign and attack the recipient's&#xD;
        body cells. &quot;Graft&quot; refers to transplanted, or donated tissues, and &quot;host&quot; refers to the&#xD;
        tissues of the recipient. It is a common complication after allogeneic HCT. The onset of&#xD;
        cGVHD is usually within three years of transplantation and has some features of autoimmune&#xD;
        diseases. A strategy that minimizes the incidence and severity of cGVHD, without other&#xD;
        adverse effects, is needed to improve survival after allogeneic HCT. T regulatory cells are&#xD;
        critical for controlling autoimmunity and maintaining immune homeostasis. Patients with&#xD;
        active cGVHD have reduced numbers of T regulatory cells compared to patients without GVHD,&#xD;
        suggesting that restoration of T regulatory cells in patients with active cGCHD is impaired&#xD;
        and insufficient numbers may contribute to cGVHD. Therefore, therapies that augment numbers&#xD;
        and function of T regulatory cells may promote tolerance and control of cGVHD. CAR T-cell&#xD;
        therapy is a type of treatment in which T cells (a type of immune system cell) are taken from&#xD;
        the blood and changed in the laboratory. The gene for a special receptor that binds to a&#xD;
        certain protein, CD6, on the patient's cells is added to the T cells in the laboratory. The&#xD;
        special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T&#xD;
        cells are grown in the laboratory and given to the patient by infusion. CD6-CAR Tregs&#xD;
        combines the CD6-targeted anti-inflammatory response with the immune regulatory properties of&#xD;
        T regulatory cells which could generate a more potent and stable T regulatory cell population&#xD;
        to promote immune tolerance and long-term disease control in cGVHD.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        PRIMARY OBJECTIVES:&#xD;
  &#xD;
        I. Determine if CD6-CAR Tregs administration is safe and tolerable in patients who developed&#xD;
        chronic graft-versus-host disease (cGVHD), by evaluation of toxicities, including: type,&#xD;
        frequency, severity, attribution, time course and duration.&#xD;
  &#xD;
        II. To evaluate the feasibility to produce donor derived CD6-CAR Tregs.&#xD;
  &#xD;
        SECONDARY OBJECTIVES:&#xD;
  &#xD;
        I. Obtain preliminary evidence of CD6-CAR Tregs activity against cGVHD by estimating the&#xD;
        response rate (as defined by 2014 National Institute of Health [NIH] consensus development&#xD;
        project on clinical trials in cGVHD).&#xD;
  &#xD;
        II. Evaluate changes in cGVHD severity using physician -reported cGVHD activity assessment&#xD;
        form.&#xD;
  &#xD;
        III. Evaluate changes in symptom activity using cGVHD activity assessment patient&#xD;
        self-report.&#xD;
  &#xD;
        IV. Evaluate failure-free survival (FFS). V. Quantify CD6-CAR Treg cells in peripheral blood.&#xD;
        VI. Characterize and assess changes in immune biomarkers over time in blood samples.&#xD;
  &#xD;
        EXPLORATORY OBJECTIVES:&#xD;
  &#xD;
        I. Percent and counts from peripheral blood T cell subsets in hematopoietic stem/progenitor&#xD;
        cell compartments to assess ability of CD6-CAR Tregs to suppress pathogenic T cell activity&#xD;
        and proliferation.&#xD;
  &#xD;
        II. Profile cytokine levels over time and changes to assess the ability of CD6-CAR Tregs to&#xD;
        down-regulate proinflammatory cytokine production (IFNgamma, IL-6, TNFalpha) and adhesion&#xD;
        molecules that promote pathogenic T cell.&#xD;
  &#xD;
        III. For subjects who receive tafasitamab-cxix for CAR Treg ablation, describe the activity&#xD;
        of infusional tafasitamab-cxix to eliminate transferred CD6 CAR Treg cells.&#xD;
  &#xD;
        OUTLINE: This is a dose-escalation study of CD6-CAR Treg cells followed by a dose-expansion&#xD;
        study.&#xD;
  &#xD;
        Donors undergo leukapheresis over 2-4 hours for collection of peripheral blood mononuclear&#xD;
        cells (PBMSc) and the manufacturing of CD6-CAR Treg cells over 2 weeks. Patients then receive&#xD;
        CD6-CAR Treg intravenously on day 0. Patients may also receive ablation tafasitamab IV post&#xD;
        Treg cell infusion on days 1, 4, 8, 15, 22 for 1 cycle. If ablation is not complete by day&#xD;
        28, patients may receive an additional 1-2 cycles per investigator's discretion. Cycles&#xD;
        repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients&#xD;
        undergo echocardiography (ECHO), computed tomography (CT), and x-ray imaging during screening&#xD;
        and as clinically indicated. Patients undergo blood specimen collection on study and during&#xD;
        follow-up. Patients may undergo a biopsy on study as well as a lumbar puncture and magnetic&#xD;
        resonance imaging (MRI)/CT as clinically indicated on study.&#xD;
  &#xD;
        After completion of study treatment, patients are followed up to 28 days, monthly for 1 year,&#xD;
        and then yearly for 15 years.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 17, 2023</start_date>
    <completion_date type="Anticipated">May 5, 2027</completion_date>
    <primary_completion_date type="Anticipated">May 5, 2027</primary_completion_date>
    <phase>Phase 1</phase>
    <study_type>Interventional</study_type>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Dose-limiting toxicity</measure>
      <time_frame>From infusion of Allogeneic CD6 chimeric antigen receptor T regulatory cells (CD6-CAR Tregs) to day +28</time_frame>
      <description>Toxicity will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0; cytokine release syndrome and immune effector cell associated neurotoxicity syndrome will be assessed per American Society for Transplantation and Cellular Therapy consensus criteria. Observed toxicities will be summarized by type, severity, date of onset, duration, reversibility, and attribution.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Feasibility as the ability to met at least 80% of the required cell dose at the assigned dose level</measure>
      <time_frame>From infusion of CD6-CAR Tregs to day +28</time_frame>
      <description>Will be estimated with 90% confidence interval (CI) overall and by dose level.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Feasibility as the ability to meet the required produce release criteria</measure>
      <time_frame>From infusion of CD6-CAR Tregs to day +28</time_frame>
      <description>Will be estimated with 90% CI overall and by dose level.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>CD6-CAR Treg activity</measure>
      <time_frame>Up to 15 years</time_frame>
      <description>As measured by changes in chronic graft versus host disease (cGVHD) severity.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in cGVHD severity</measure>
      <time_frame>Baseline up to 15 years</time_frame>
      <description>Will be evaluated using cGVHD activity assessment patient self-report. Various graphical methods will be used to explore the association between immune response measures (at different time points and the changes over time) with changes in cGVHD severity.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Failure-free survival (FFS)</measure>
      <time_frame>From infusion of CD6-CAR Tregs to start of new treatment for cGVHD, recurrence of malignancy, or death, whichever comes first, assessed at week 12 and 1-year follow-up</time_frame>
      <description>Kaplan-Meier curve will be used to estimate FFS.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Relapse-free survival</measure>
      <time_frame>From the start of treatment to the date of death, disease relapse, or last follow-up whichever occurs first, assessed up to 15 years</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>CD6-CAR Treg persistence</measure>
      <time_frame>Up to 15 years</time_frame>
      <description>Immunophenotyping (CD19t, CD3, CD4, CD8) (fluorescence-activated cell sorting/ co-detection by indexing), cytokine release syndrome (including TNF-alpha, IL-2, IL-6, IL-10 and IFN-gamma) (multiplex assay), immunogenicity (anti-CAR antibodies) (enzyme-linked immunosorbent assay)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in immune biomarkers over time</measure>
      <time_frame>Baseline up to 15 years</time_frame>
      <description>Descriptive statistics and graphics will be used to characterize and plot the specific time trend for each marker of the immune response. Various graphical methods will be used to explore the association between these immune response measures (at different time points and the changes over time) with changes in cGVHD severity.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Infectious complications</measure>
      <time_frame>From day 1 to day 28 of CD6-CAR Treg infusion, up to 15 years</time_frame>
      <description>Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. This data will be captured via case report form and will be collected from day 1 to day 28 of alloCD6-CAR Treg infusion and will follow the same data collection intervals as the toxicity and adverse event data. Severity of the infections will be graded by CTCAE v5.0 and Blood and Marrow Clinical Trials Network.</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">27</enrollment>
    <condition>Chronic Graft Versus Host Disease</condition>
    <condition>Hematologic and Lymphocytic Disorder</condition>
    <condition>Steroid Refractory Graft Versus Host Disease</condition>
    <arm_group>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Donors undergo leukapheresis over 2-4 hours for collection of PBMSc and the manufacturing of CD6-CAR Treg cells over 2 weeks. Patients then receive CD6-CAR Treg intravenously on day 0. Patients may also receive ablation tafasitamab IV post Treg cell infusion on days 1, 4, 8, 15, 22 for 1 cycle. If ablation is not complete by day 28, patients may receive an additional 1-2 cycles per investigator's discretion. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, CT, and x-ray imaging during screening and as clinically indicated. Patients undergo blood specimen collection on study and during follow-up. Patients may undergo a biopsy on study as well as a lumbar puncture and MRI/CT as clinically indicated on study.</description>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Biopsy</intervention_name>
      <description>Undergo biopsy</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <other_name>BIOPSY_TYPE</other_name>
      <other_name>Bx</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Biospecimen Collection</intervention_name>
      <description>Undergo blood sample collection</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</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>Biological</intervention_type>
      <intervention_name>Chimeric Antigen Receptor T-Cell Therapy</intervention_name>
      <description>Given CD6-CAR Tregs IV</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <other_name>CAR T Infusion</other_name>
      <other_name>CAR T Therapy</other_name>
      <other_name>CAR T-cell Therapy</other_name>
      <other_name>Chimeric Antigen Receptor T-cell Infusion</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Computed Tomography</intervention_name>
      <description>Undergo CT</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</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>Procedure</intervention_type>
      <intervention_name>Echocardiography</intervention_name>
      <description>Undergo ECHO</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <other_name>EC</other_name>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Electronic Health Record Review</intervention_name>
      <description>Ancillary studies</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Leukapheresis</intervention_name>
      <description>Undergo leukapheresis</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <other_name>Leukocytopheresis</other_name>
      <other_name>Therapeutic Leukopheresis</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Lumbar Puncture</intervention_name>
      <description>Undergo lumbar puncture</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <other_name>LP</other_name>
      <other_name>Spinal Tap</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Magnetic Resonance Imaging</intervention_name>
      <description>Undergo MRI/CT</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</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>Other</intervention_type>
      <intervention_name>Quality-of-Life Assessment</intervention_name>
      <description>Ancillary studies</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <other_name>Quality of Life Assessment</other_name>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Tafasitamab</intervention_name>
      <description>Given IV</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <other_name>Immunoglobulin, Anti-(Human Cd19 Antigen) (Human-mus musculus Monoclonal MOR00208 Heavy Chain), Disulfide with Human-mus musculus Monoclonal MOR00208 .Kappa.-chain, Dimer</other_name>
      <other_name>Monjuvi</other_name>
      <other_name>MOR-00208</other_name>
      <other_name>MOR00208</other_name>
      <other_name>MOR208</other_name>
      <other_name>Tafasitamab-cxix</other_name>
      <other_name>XmAb5574</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>X-Ray Imaging</intervention_name>
      <description>Undergo x-ray imaging</description>
      <arm_group_label>Treatment (CD6-CAR Treg, tafasitamab)</arm_group_label>
      <other_name>Conventional X-Ray</other_name>
      <other_name>Diagnostic Radiology</other_name>
      <other_name>Medical Imaging, X-Ray</other_name>
      <other_name>Plain film radiographs</other_name>
      <other_name>Radiographic Imaging</other_name>
      <other_name>Radiographic imaging procedure (procedure)</other_name>
      <other_name>Radiography</other_name>
      <other_name>RG</other_name>
      <other_name>Static X-Ray</other_name>
      <other_name>X-Ray</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  PATIENT (RECIPIENT) INCLUSION CRITERIA:&#xD;
  &#xD;
            -  All participants must have the ability to understand and the willingness to sign a&#xD;
               written informed consent&#xD;
  &#xD;
            -  Participants must agree to allow the use of archival tissue from diagnostic biopsies.&#xD;
  &#xD;
                 -  If unavailable, exceptions may be granted with study PI approval Note: For&#xD;
                    research participants who do not speak English, a short form consent may be used&#xD;
                    with a City of Hope (COH) certified interpreter/translator to proceed with&#xD;
                    screening and leukapheresis, while the request for a translated full consent is&#xD;
                    processed&#xD;
  &#xD;
            -  Age &gt;= 18 years&#xD;
  &#xD;
            -  Karnofsky performance status of &gt;= 70%&#xD;
  &#xD;
            -  Received allogeneic hematopoietic stem cell transplantation (alloHCT) from matched&#xD;
               related or haploidentical donor as part of treatment of hematologic disorders Note:&#xD;
               The donor needs to consent for leukapheresis&#xD;
  &#xD;
            -  Clinical diagnosis of steroid-dependent or refractory, moderate to severe cGVHD&#xD;
  &#xD;
                 -  Steroid refractory cGVHD defined as having persistent signs and symptoms of cGVHD&#xD;
                    per institutional policy despite the use of prednisone for 2 months without&#xD;
                    complete resolution of signs and symptoms&#xD;
  &#xD;
            -  Estimated life expectancy &gt; 90 days&#xD;
  &#xD;
            -  Stable dose of corticosteroids for &gt;= 14 days prior to enrollment not exceeding&#xD;
               15mg/day of prednisone or equivalent + with up to 7ng/mL/day sirolimus with&#xD;
               therapeutic drug monitoring&#xD;
  &#xD;
            -  Exposure to at least 1 of the Food and Drug Administration (FDA) approved tyrosine&#xD;
               kinase inhibitor (TKI) therapies for cGVHD&#xD;
  &#xD;
            -  Naive to anti-CD6 therapy post most recent alloHCT&#xD;
  &#xD;
            -  Absolute neutrophil count (ANC) &gt;= 1,000/mm^3 (without myeloid growth factors within 1&#xD;
               week of study entry) (performed within 28 days prior to enrollment)&#xD;
  &#xD;
            -  Platelets &gt;= 50,000/mm^3 (performed within 28 days prior to enrollment) NOTE: Platelet&#xD;
               transfusions are not permitted within 14 days of platelet assessment&#xD;
  &#xD;
            -  Total bilirubin =&lt; 2 mg/dL (exception permitted in patients with Gilbert's syndrome),&#xD;
               unless hepatic dysfunction is a manifestation of presumed cGVHD) (performed within 28&#xD;
               days prior to enrollment) NOTE: Abnormal liver function tests (LFTs) (liver function&#xD;
               panel) in the context of active cGVHD involving other organ systems may also be&#xD;
               permitted if the treating physician documents the abnormal LFTs as being consistent&#xD;
               with hepatic cGVHD and a liver biopsy will not be mandated in this situation&#xD;
  &#xD;
            -  Aspartate aminotransferase (AST) =&lt; 3.0 x upper limit of normal (ULN) (performed&#xD;
               within 28 days prior to enrollment)&#xD;
  &#xD;
            -  Alanine aminotransferase (ALT) =&lt; 3.0 x ULN (performed within 28 days prior to&#xD;
               enrollment)&#xD;
  &#xD;
            -  Creatinine clearance of &gt;= 30 mL/min per 24-hour urine test or the Cockcroft-Gault&#xD;
               formula (performed within 28 days prior to enrollment)&#xD;
  &#xD;
            -  Seronegative for human immunodeficiency virus (HIV) antigen/antibody (Ag/Ab) combo,&#xD;
               hepatitis C virus (HCV)*, active hepatitis B virus (HBV) (surface antigen negative),&#xD;
               and syphilis (rapid plasma reagin [RPR]) (performed within 28 days prior to&#xD;
               enrollment)&#xD;
  &#xD;
                 -  If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed OR&#xD;
  &#xD;
                 -  If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed.&#xD;
                    Viral load must be undetectable&#xD;
  &#xD;
            -  Subjects must have negative QuantiFERON-tuberculosis (TB) Gold (QFTG) test (performed&#xD;
               within 28 days prior to enrollment). Patients with positive QFTG test need clearance&#xD;
               from infectious disease (ID) before enrollment&#xD;
  &#xD;
            -  Negative for coronavirus disease 2019 (COVID-19) within 72 hours of day 0 of protocol&#xD;
               therapy (performed within 28 days prior to enrollment)&#xD;
  &#xD;
            -  Meets other institutional and federal requirements for infectious disease titer&#xD;
               requirements Note Infectious disease testing to be performed within 28 days prior to&#xD;
               start of protocol therapy&#xD;
  &#xD;
            -  Women of childbearing potential (WOCBP): negative urine or serum pregnancy test&#xD;
               (performed within 28 days prior to enrollment) Note: If the urine test is positive or&#xD;
               cannot be confirmed as negative, a serum pregnancy test will be required&#xD;
  &#xD;
            -  Cardiac function (12 lead-electrocardiography [ECG]): corrected QT interval (QTc) must&#xD;
               be =&lt; 480 msec (performed within 28 days prior to enrollment)&#xD;
  &#xD;
            -  Left ventricular ejection fraction &gt; 40% (performed within 28 days prior to&#xD;
               enrollment)&#xD;
  &#xD;
            -  Oxygen saturation 92% or above at room air or carbon monoxide diffusing capability&#xD;
               test (DLCO) of 40% of best predicted (performed within 28 days prior to enrollment)&#xD;
               Note: The above criteria only applies to participants who are not experiencing lung&#xD;
               GVHD bronchiolitis obliterans syndrome (BOS)&#xD;
  &#xD;
            -  Agreement by females and males of childbearing potential* to use an effective method&#xD;
               of birth control** or abstinence from sexual activity for the course of the study&#xD;
               through at least 6 months after the last dose of protocol therapy.&#xD;
  &#xD;
                 -  Childbearing potential defined as not being surgically sterilized (men and women)&#xD;
                    or have not been free from menses for &gt; 1 year (women only)&#xD;
  &#xD;
                      -  Effective birth control defined as hormonal and/or barrier contraception)&#xD;
  &#xD;
            -  ALLOGENEIC DONOR CRITERIA FOR APHERESIS DONATION:&#xD;
  &#xD;
            -  The identified donor must be the original donor whose stem cells were used for the&#xD;
               research participant's alloSCT&#xD;
  &#xD;
            -  Karnofsky Performance Status (KPS) &gt;= 70&#xD;
  &#xD;
            -  Age: &gt;= 18 years&#xD;
  &#xD;
            -  The donor is approved and has completed the donor evaluation per institutional&#xD;
               guidelines (as indicated in DACT 122 - Administrative Protocol for Allogeneic&#xD;
               Hematopoietic Progenitor Cell, Apheresis [HPC(A)] Collections). Additionally, donor&#xD;
               will also be screened for the following infectious diseases:&#xD;
  &#xD;
                 -  Epstein-Barr virus (EBV),&#xD;
  &#xD;
                 -  Human herpes virus 6, 7, and 8 (HHV6, HHV7, HHV8)&#xD;
  &#xD;
                 -  Parvovirus B19 Note: ID test results for EBV, HHV6, HHV7, HHV8 and Parvovirus B19&#xD;
                    are not necessary to proceed with the apheresis procedure but do have to be&#xD;
                    resulted and negative before participant CAR Treg infusion&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  PATIENT (RECIPIENT) EXCLUSION CRITERIA:&#xD;
  &#xD;
            -  Immunosuppressive therapy within 28 days prior to enrollment (exception:&#xD;
               corticosteroid)&#xD;
  &#xD;
            -  Concurrent other investigational agents, including biologics&#xD;
  &#xD;
            -  Vaccines within 28 days prior to enrollment&#xD;
  &#xD;
            -  Donor lymphocyte infusion within 100 days of enrollment&#xD;
  &#xD;
            -  No known contraindications to steroids or tocilizumab&#xD;
  &#xD;
            -  No current active malignancy* (Exception: Basal or squamous cell carcinoma)&#xD;
  &#xD;
            -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
               composition to study agent&#xD;
  &#xD;
            -  Active uncontrolled infection requiring systemic antibiotics and/or anti-virals&#xD;
  &#xD;
            -  Other autoimmune/inflammatory disorders&#xD;
  &#xD;
            -  Clinically significant uncontrolled illness&#xD;
  &#xD;
            -  History of vascular disease (e.g., deep vein thrombosis, stroke)&#xD;
  &#xD;
            -  Unstable cardiac disease as defined by one of the following:&#xD;
  &#xD;
                 -  Cardiac events such as myocardial infarction (MI) within the past 6 months&#xD;
  &#xD;
                 -  NYHA (New York Heart Association) heart failure class III-IV&#xD;
  &#xD;
                 -  Uncontrolled atrial fibrillation or hypertension&#xD;
  &#xD;
            -  Females only: Pregnant or breastfeeding&#xD;
  &#xD;
            -  Inability to comply with protocol therapy and follow up visits&#xD;
  &#xD;
            -  Prospective participants who, in the opinion of the investigator, may not be able to&#xD;
               comply with all study procedures (including compliance issues related to&#xD;
               feasibility/logistics)&#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>Amandeep Salhotra</last_name>
      <role>Principal Investigator</role>
      <affiliation>City of Hope Medical Center</affiliation>
    </overall_official>
    <location>
      <facility>
        <name>City of Hope Medical Center</name>
        <address>
          <city>Duarte</city>
          <state>California</state>
          <zip>91010</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Amandeep Salhotra</last_name>
        <phone>626-218-2405</phone>
        <email>asalhotra@coh.org</email>
      </contact>
      <investigator>
        <last_name>Amandeep Salhotra</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 7, 2023</study_first_submitted>
    <study_first_submitted_qc>August 7, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 15, 2023</study_first_posted>
    <last_update_submitted>August 7, 2023</last_update_submitted>
    <last_update_submitted_qc>August 7, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 15, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Bronchiolitis Obliterans Syndrome</mesh_term>
      <mesh_term>Hematologic Diseases</mesh_term>
      <mesh_term>Graft vs Host Disease</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Immunoglobulins</mesh_term>
    </intervention_browse>
    <!-- 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/NCT05993611
  org study id: 22375
  secondary id: NCI-2023-04067
  secondary id: 22375
  secondary id: P30CA033572
  nct id: NCT05993611
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  This phase I trial tests the safety, side effects, and best dose of allogeneic CD6 chimeric
        antigen receptor T regulatory cells (CD6-CAR Tregs) in treating patients who have chronic
        graft versus host disease (cGVHD) after an allogeneic hematopoietic cell transplantation
        (HCT). An allogeneic HCT is an established treatment for benign or malignant blood and marrow
        conditions where healthy stem cells from a donor are infused into a patient to help the
        patient's bone marrow make more healthy cells and platelets. GVHD is a systemic disorder that
        occurs when the graft's immune cells recognize the host as foreign and attack the recipient's
        body cells. "Graft" refers to transplanted, or donated tissues, and "host" refers to the
        tissues of the recipient. It is a common complication after allogeneic HCT. The onset of
        cGVHD is usually within three years of transplantation and has some features of autoimmune
        diseases. A strategy that minimizes the incidence and severity of cGVHD, without other
        adverse effects, is needed to improve survival after allogeneic HCT. T regulatory cells are
        critical for controlling autoimmunity and maintaining immune homeostasis. Patients with
        active cGVHD have reduced numbers of T regulatory cells compared to patients without GVHD,
        suggesting that restoration of T regulatory cells in patients with active cGCHD is impaired
        and insufficient numbers may contribute to cGVHD. Therefore, therapies that augment numbers
        and function of T regulatory cells may promote tolerance and control of cGVHD. CAR T-cell
        therapy is a type of treatment in which T cells (a type of immune system cell) are taken from
        the blood and changed in the laboratory. The gene for a special receptor that binds to a
        certain protein, CD6, on the patient's cells is added to the T cells in the laboratory. The
        special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T
        cells are grown in the laboratory and given to the patient by infusion. CD6-CAR Tregs
        combines the CD6-targeted anti-inflammatory response with the immune regulatory properties of
        T regulatory cells which could generate a more potent and stable T regulatory cell population
        to promote immune tolerance and long-term disease control in cGVHD.
  PRIMARY OBJECTIVES:
  
        I. Determine if CD6-CAR Tregs administration is safe and tolerable in patients who developed
        chronic graft-versus-host disease (cGVHD), by evaluation of toxicities, including: type,
        frequency, severity, attribution, time course and duration.
  
        II. To evaluate the feasibility to produce donor derived CD6-CAR Tregs.
  
        SECONDARY OBJECTIVES:
  
        I. Obtain preliminary evidence of CD6-CAR Tregs activity against cGVHD by estimating the
        response rate (as defined by 2014 National Institute of Health [NIH] consensus development
        project on clinical trials in cGVHD).
  
        II. Evaluate changes in cGVHD severity using physician -reported cGVHD activity assessment
        form.
  
        III. Evaluate changes in symptom activity using cGVHD activity assessment patient
        self-report.
  
        IV. Evaluate failure-free survival (FFS). V. Quantify CD6-CAR Treg cells in peripheral blood.
        VI. Characterize and assess changes in immune biomarkers over time in blood samples.
  
        EXPLORATORY OBJECTIVES:
  
        I. Percent and counts from peripheral blood T cell subsets in hematopoietic stem/progenitor
        cell compartments to assess ability of CD6-CAR Tregs to suppress pathogenic T cell activity
        and proliferation.
  
        II. Profile cytokine levels over time and changes to assess the ability of CD6-CAR Tregs to
        down-regulate proinflammatory cytokine production (IFNgamma, IL-6, TNFalpha) and adhesion
        molecules that promote pathogenic T cell.
  
        III. For subjects who receive tafasitamab-cxix for CAR Treg ablation, describe the activity
        of infusional tafasitamab-cxix to eliminate transferred CD6 CAR Treg cells.
  
        OUTLINE: This is a dose-escalation study of CD6-CAR Treg cells followed by a dose-expansion
        study.
  
        Donors undergo leukapheresis over 2-4 hours for collection of peripheral blood mononuclear
        cells (PBMSc) and the manufacturing of CD6-CAR Treg cells over 2 weeks. Patients then receive
        CD6-CAR Treg intravenously on day 0. Patients may also receive ablation tafasitamab IV post
        Treg cell infusion on days 1, 4, 8, 15, 22 for 1 cycle. If ablation is not complete by day
        28, patients may receive an additional 1-2 cycles per investigator's discretion. Cycles
        repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients
        undergo echocardiography (ECHO), computed tomography (CT), and x-ray imaging during screening
        and as clinically indicated. Patients undergo blood specimen collection on study and during
        follow-up. Patients may undergo a biopsy on study as well as a lumbar puncture and magnetic
        resonance imaging (MRI)/CT as clinically indicated on study.
  
        After completion of study treatment, patients are followed up to 28 days, monthly for 1 year,
        and then yearly for 15 years.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Dose-limiting toxicity
  time frame: From infusion of Allogeneic CD6 chimeric antigen receptor T regulatory cells (CD6-CAR Tregs) to day +28
  description: Toxicity will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0; cytokine release syndrome and immune effector cell associated neurotoxicity syndrome will be assessed per American Society for Transplantation and Cellular Therapy consensus criteria. Observed toxicities will be summarized by type, severity, date of onset, duration, reversibility, and attribution.
  measure: Feasibility as the ability to met at least 80% of the required cell dose at the assigned dose level
  time frame: From infusion of CD6-CAR Tregs to day +28
  description: Will be estimated with 90% confidence interval (CI) overall and by dose level.
  measure: Feasibility as the ability to meet the required produce release criteria
  time frame: From infusion of CD6-CAR Tregs to day +28
  description: Will be estimated with 90% CI overall and by dose level.
  measure: CD6-CAR Treg activity
  time frame: Up to 15 years
  description: As measured by changes in chronic graft versus host disease (cGVHD) severity.
  measure: Changes in cGVHD severity
  time frame: Baseline up to 15 years
  description: Will be evaluated using cGVHD activity assessment patient self-report. Various graphical methods will be used to explore the association between immune response measures (at different time points and the changes over time) with changes in cGVHD severity.
  measure: Failure-free survival (FFS)
  time frame: From infusion of CD6-CAR Tregs to start of new treatment for cGVHD, recurrence of malignancy, or death, whichever comes first, assessed at week 12 and 1-year follow-up
  description: Kaplan-Meier curve will be used to estimate FFS.
  measure: Relapse-free survival
  time frame: From the start of treatment to the date of death, disease relapse, or last follow-up whichever occurs first, assessed up to 15 years
  measure: CD6-CAR Treg persistence
  time frame: Up to 15 years
  description: Immunophenotyping (CD19t, CD3, CD4, CD8) (fluorescence-activated cell sorting/ co-detection by indexing), cytokine release syndrome (including TNF-alpha, IL-2, IL-6, IL-10 and IFN-gamma) (multiplex assay), immunogenicity (anti-CAR antibodies) (enzyme-linked immunosorbent assay)
  measure: Changes in immune biomarkers over time
  time frame: Baseline up to 15 years
  description: Descriptive statistics and graphics will be used to characterize and plot the specific time trend for each marker of the immune response. Various graphical methods will be used to explore the association between these immune response measures (at different time points and the changes over time) with changes in cGVHD severity.
  measure: Infectious complications
  time frame: From day 1 to day 28 of CD6-CAR Treg infusion, up to 15 years
  description: Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. This data will be captured via case report form and will be collected from day 1 to day 28 of alloCD6-CAR Treg infusion and will follow the same data collection intervals as the toxicity and adverse event data. Severity of the infections will be graded by CTCAE v5.0 and Blood and Marrow Clinical Trials Network.
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  arm group type: Experimental
  description: Donors undergo leukapheresis over 2-4 hours for collection of PBMSc and the manufacturing of CD6-CAR Treg cells over 2 weeks. Patients then receive CD6-CAR Treg intravenously on day 0. Patients may also receive ablation tafasitamab IV post Treg cell infusion on days 1, 4, 8, 15, 22 for 1 cycle. If ablation is not complete by day 28, patients may receive an additional 1-2 cycles per investigator's discretion. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, CT, and x-ray imaging during screening and as clinically indicated. Patients undergo blood specimen collection on study and during follow-up. Patients may undergo a biopsy on study as well as a lumbar puncture and MRI/CT as clinically indicated on study.
  intervention type: Procedure
  intervention name: Biopsy
  description: Undergo biopsy
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: BIOPSY_TYPE
  other name: Bx
  intervention type: Procedure
  intervention name: Biospecimen Collection
  description: Undergo blood sample collection
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: Biological Sample Collection
  other name: Biospecimen Collected
  other name: Specimen Collection
  intervention type: Biological
  intervention name: Chimeric Antigen Receptor T-Cell Therapy
  description: Given CD6-CAR Tregs IV
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: CAR T Infusion
  other name: CAR T Therapy
  other name: CAR T-cell Therapy
  other name: Chimeric Antigen Receptor T-cell Infusion
  intervention type: Procedure
  intervention name: Computed Tomography
  description: Undergo CT
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  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: Procedure
  intervention name: Echocardiography
  description: Undergo ECHO
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: EC
  intervention type: Other
  intervention name: Electronic Health Record Review
  description: Ancillary studies
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  intervention type: Procedure
  intervention name: Leukapheresis
  description: Undergo leukapheresis
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: Leukocytopheresis
  other name: Therapeutic Leukopheresis
  intervention type: Procedure
  intervention name: Lumbar Puncture
  description: Undergo lumbar puncture
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: LP
  other name: Spinal Tap
  intervention type: Procedure
  intervention name: Magnetic Resonance Imaging
  description: Undergo MRI/CT
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  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: Other
  intervention name: Quality-of-Life Assessment
  description: Ancillary studies
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: Quality of Life Assessment
  intervention type: Biological
  intervention name: Tafasitamab
  description: Given IV
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: Immunoglobulin, Anti-(Human Cd19 Antigen) (Human-mus musculus Monoclonal MOR00208 Heavy Chain), Disulfide with Human-mus musculus Monoclonal MOR00208 .Kappa.-chain, Dimer
  other name: Monjuvi
  other name: MOR-00208
  other name: MOR00208
  other name: MOR208
  other name: Tafasitamab-cxix
  other name: XmAb5574
  intervention type: Procedure
  intervention name: X-Ray Imaging
  description: Undergo x-ray imaging
  arm group label: Treatment (CD6-CAR Treg, tafasitamab)
  other name: Conventional X-Ray
  other name: Diagnostic Radiology
  other name: Medical Imaging, X-Ray
  other name: Plain film radiographs
  other name: Radiographic Imaging
  other name: Radiographic imaging procedure (procedure)
  other name: Radiography
  other name: RG
  other name: Static X-Ray
  other name: X-Ray
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Amandeep Salhotra
  role: Principal Investigator
  affiliation: City of Hope Medical Center
  facility: 
  contact: 
  investigator: 
  country: United States
  responsible party type: Sponsor
  mesh term: Bronchiolitis Obliterans Syndrome
  mesh term: Hematologic Diseases
  mesh term: Graft vs Host Disease
  mesh term: Immunoglobulins