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/NCT05976555</url>
    </required_header>
    <id_info>
      <org_study_id>IIT-DHAKAL-TGF-BETA-BCMA</org_study_id>
      <nct_id>NCT05976555</nct_id>
    </id_info>
    <brief_title>Phase I Trial of BCMA-TGF-BETA CAR-T Cells in Relapsed, Refractory Myeloma</brief_title>
    <official_title>Phase I Study of BCMA-TGF-BETA Insensitive Armored CAR T Cells in Patients With Relapsed and/or Refractory Multiple Myeloma</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Medical College of Wisconsin</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Medical College of Wisconsin</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>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This is a phase I, interventional, single-arm, open-label, dose-finding treatment study&#xD;
        designed to evaluate the safety and efficacy of interleukin-7(IL-7) / interleukin-15 (IL-15)&#xD;
        manufactured CAR T cells in adult patients with relapsed and/or refractory myeloma that have&#xD;
        failed prior therapies.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        BCMA-Transforming growth factor-beta (TGFβ) CAR-T cells will be administered either fresh or&#xD;
        thawed after cryopreservation by IV injection. Patients will receive one of three dose levels&#xD;
        of BCMA-TGFβ CAR-T cells based on our dose escalation design.&#xD;
  &#xD;
        After the maximal tolerated dose (MTD) is determined, an additional dose-expansion cohort of&#xD;
        up to 9 patients (3 BCMA-naïve and 6 BCMA exposed) may be enrolled at that dose to further&#xD;
        describe the safety and preliminary efficacy of that dose.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 2023</start_date>
    <completion_date type="Anticipated">November 2028</completion_date>
    <primary_completion_date type="Anticipated">November 2026</primary_completion_date>
    <phase>Phase 1</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Sequential Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Number of Adverse Events After BCMA-TGFβ CAR-T Cell Infusion</measure>
      <time_frame>from infusion until Day +28 post CAR T infusion</time_frame>
      <description>Incidence of adverse events with grade 3 to 5 severity using NCI CTCAE version 5.0 and the Lee et al. consensus manuscript (which outlines the defining characteristics of each grade for cytokine release syndrome; please refer to the reference below).</description>
    </primary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">24</enrollment>
    <condition>Multiple Myeloma</condition>
    <arm_group>
      <arm_group_label>BCMA-TGFβ CAR-T cells (0.75 x10^6 cells/kg)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>BCMA-TGFβ CAR-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Subjects will receive one of three dose levels of BCMA-TGFβ CAR-T cells based on the dose escalation design.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>BCMA-TGFβ CAR-T cells (1 x 10^6 cells/kg)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>BCMA-TGFβ CAR-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Subjects will receive one of three dose levels of BCMA-TGFβ CAR-T cells based on the dose escalation design.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>BCMA-TGFβ CAR-T cells (2.5 x 10^6 cells/kg)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>BCMA-TGFβ CAR-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Subjects will receive one of three dose levels of BCMA-TGFβ CAR-T cells based on the dose escalation design.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>BCMA-TGFβ CAR-T cells (Maximum tolerated dose)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>After the maximal tolerated dose (MTD) is determined, an additional dose-expansion cohort of up to 9 patients (3 BCMA-naïve and 6 BCMA exposed) may be enrolled at that dose.</description>
    </arm_group>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>BCMA-TGFβ CAR-T cells (0.75 x10^6 cells/kg)</intervention_name>
      <description>This is dose level -1.</description>
      <arm_group_label>BCMA-TGFβ CAR-T cells (0.75 x10^6 cells/kg)</arm_group_label>
      <arm_group_label>BCMA-TGFβ CAR-T cells (Maximum tolerated dose)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>BCMA-TGFβ CAR-T cells (1 x 10^6 cells/kg)</intervention_name>
      <description>This is the starting dose (dose level 0).</description>
      <arm_group_label>BCMA-TGFβ CAR-T cells (1 x 10^6 cells/kg)</arm_group_label>
      <arm_group_label>BCMA-TGFβ CAR-T cells (Maximum tolerated dose)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>BCMA-TGFβ CAR-T cells (2.5 x 10^6 cells/kg)</intervention_name>
      <description>This is dose level 1.</description>
      <arm_group_label>BCMA-TGFβ CAR-T cells (2.5 x 10^6 cells/kg)</arm_group_label>
      <arm_group_label>BCMA-TGFβ CAR-T cells (Maximum tolerated dose)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Maximum tolerated dose</intervention_name>
      <description>The maximum tolerated dose is yet to be determined.</description>
      <arm_group_label>BCMA-TGFβ CAR-T cells (Maximum tolerated dose)</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Patients must be aged ≥18 years to 80 years old.&#xD;
  &#xD;
            2. Patients must have received three prior lines of therapies, including proteasome&#xD;
               inhibitor, immunomodulator and a cluster of differentiation (CD) 38 monoclonal&#xD;
               antibody:&#xD;
  &#xD;
               • International Myeloma Working Group (IMWG) criteria defines refractory disease as&#xD;
               disease progression on or within 60 days of receiving therapy.&#xD;
  &#xD;
            3. Patients must have measurable disease, including at least one or more of the following&#xD;
               criteria:&#xD;
  &#xD;
                 1. Serum M-protein ≥0.5 g/dl;&#xD;
  &#xD;
                 2. Urine M-protein ≥200 mg/24 hrs;&#xD;
  &#xD;
                 3. Involved serum light chain ≥100 mg/L with abnormal light chain ratio;&#xD;
  &#xD;
            4. Absolute CD 3 count ≥50 mm^3.&#xD;
  &#xD;
            5. Karnofsky performance score ≥70.&#xD;
  &#xD;
            6. Adequate hepatic function, defined as:&#xD;
  &#xD;
                 1. aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline&#xD;
                    phosphatase &lt;3x upper limit of normal (ULN);&#xD;
  &#xD;
                 2. Serum bilirubin &lt;2.0 mg/dL except for patients with Gilbert's syndrome, who must&#xD;
                    have serum bilirubin of &lt;3 mg/dL.&#xD;
  &#xD;
            7. Absolute neutrophil count (ANC) ≥1,000 with no Granulocyte colony-stimulating factor&#xD;
               (G-CSF) within 72 hours or pegylated G-CSF within 10 days.&#xD;
  &#xD;
            8. Platelets ≥50,000/µL with no transfusion within 72 hours of eligibility testing.&#xD;
  &#xD;
            9. Adequate renal function, defined as creatinine clearance ≥50 mL/min calculated using&#xD;
               the Cockroft-Gault formula.&#xD;
  &#xD;
           10. Able to provide written informed consent.&#xD;
  &#xD;
           11. Agree to practice birth control during the study.&#xD;
  &#xD;
           12. Adequate cardiac function as indicated by New York Heart Association (NYHA)&#xD;
               classification I or II AND left ventricular ejection fraction of ≥45% (by cardiac&#xD;
               echocardiogram (ECHO) or multigated acquisition (MUGA)) and adequate pulmonary&#xD;
               function as indicated by room air oxygen saturation of ≥90%.&#xD;
  &#xD;
           13. Expected survival &gt;12 weeks.&#xD;
  &#xD;
           14. Negative urine or serum pregnancy test in females of childbearing potential at study&#xD;
               entry.&#xD;
  &#xD;
           15. Meet criteria for regarding fertility and contraception detailed below.&#xD;
  &#xD;
           16. No contraindication to central line access.&#xD;
  &#xD;
          Phase I Dose-Expansion Cohort A: BCMA Naïve The inclusion criteria for dose-expansion&#xD;
          Cohort A are the same as that listed above but are limited to BCMA naïve patients.&#xD;
  &#xD;
          Phase I Dose-Expansion Cohort B: BCMA Exposed The inclusion criteria for dose expansion&#xD;
          Cohort B are the same as that above but require prior exposure to BCMA directed therapies&#xD;
          (e.g., CAR-BCMA, bispecific T/ Natural Killer (NK) cell engagers of BCMA).&#xD;
  &#xD;
          Patients with prior antibody drug conjugate, bispecific T and NK cell engager and prior&#xD;
          gene-modified cellular immune therapy against BCMA are allowed. Patients must be &gt; 3 months&#xD;
          out from therapy and must have achieved stable disease or better with prior BCMA-directed&#xD;
          therapy.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Positive beta- Human chorionic gonadotropin (HCG) in female of child-bearing potential&#xD;
               defined as per the Schedule of Events table.&#xD;
  &#xD;
            2. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.&#xD;
  &#xD;
            3. History of significant autoimmune disease OR active, uncontrolled autoimmune&#xD;
               phenomenon requiring steroid therapy defined as &gt;20 mg of prednisone or equivalent&#xD;
               daily.&#xD;
  &#xD;
            4. Presence of ≥ Grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any&#xD;
               previous treatment unless it is felt to be due to underlying disease.&#xD;
  &#xD;
            5. Concurrent use of investigational therapeutic agents or enrollment on another&#xD;
               therapeutic clinical trial at any institution. Minimum of 14 days or 5 half-lives of&#xD;
               the drug (whichever is shorter) washout prior to apheresis.&#xD;
  &#xD;
            6. Refusal to participate in the long-term follow-up protocol.&#xD;
  &#xD;
            7. Patients with active central nervous system (CNS) involvement by malignancy on MRI or&#xD;
               by lumbar puncture.&#xD;
  &#xD;
               a. Patients with prior CNS disease that has been effectively treated will be eligible&#xD;
               providing last treatment was ≥2 weeks before apheresis and a remission documented&#xD;
               within 4 weeks of planned CAR T-cell infusion by MRI brain and CSF analysis.&#xD;
  &#xD;
            8. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are&#xD;
               excluded if they are &lt;6 months post-transplant, have evidence of active&#xD;
               graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.&#xD;
  &#xD;
            9. Plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, and AL&#xD;
               amyloidosis.&#xD;
  &#xD;
           10. Prior treatment with gene therapy or any gene modified cellular therapy (only&#xD;
               permitted in cohort B for the dose expansion phase).&#xD;
  &#xD;
           11. Prior BCMA-directed therapy (only permitted in cohort B for the dose expansion phase).&#xD;
  &#xD;
           12. Cytotoxic chemotherapy, oral chemotherapeutic agents, or antibody-directed treatment&#xD;
               within 14 days of apheresis or after apheresis.&#xD;
  &#xD;
                 1. Corticosteroids are allowable up until 7 days prior to apheresis and after&#xD;
                    apheresis for disease control up until the day prior to cell infusion (Day -1).&#xD;
  &#xD;
                 2. Radiation is allowed to a single symptomatic site.&#xD;
  &#xD;
           13. Patients post solid organ transplant who develop high grade lymphomas or leukemias.&#xD;
  &#xD;
           14. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.&#xD;
  &#xD;
           15. Active bacterial, viral, or fungal infection requiring systemic treatment.&#xD;
  &#xD;
           16. Patients who have received major surgery 1 week prior to leukapheresis and 3 weeks&#xD;
               prior to lymphodepletion.&#xD;
  &#xD;
           17. Active malignancy that required therapy in the last 2 years except successfully&#xD;
               treated non metastatic basal or squamous cell carcinoma, or prostate carcinoma that&#xD;
               does not require therapy. Other similar conditions may be discussed with and permitted&#xD;
               by the medical monitor.&#xD;
  &#xD;
          Special Criteria Regarding Fertility and Contraception&#xD;
  &#xD;
          Female subjects of reproductive potential (women who have reached menarche or women who&#xD;
          have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses&#xD;
          within the preceding 24 months, or have not undergone a sterilization procedure&#xD;
          [hysterectomy or bilateral oophorectomy]) must have a negative serum or urine pregnancy&#xD;
          test performed as part of eligibility criteria. Lactating women are eligible for this study&#xD;
          but will be asked to not provide breast milk to their child from Day -4 through Day +90&#xD;
          after CAR T-cell therapy.&#xD;
  &#xD;
          Due to the high-risk level of this study, while enrolled, all subjects must agree not to&#xD;
          participate in a conception process (e.g., active attempt to become pregnant or to&#xD;
          impregnate, sperm donation, in vitro fertilization). Additionally, if participating in&#xD;
          sexual activity that could lead to pregnancy, the study subject must agree to use reliable&#xD;
          and double barrier methods of contraception during the follow-up period of the protocol.&#xD;
  &#xD;
          Acceptable birth control includes a combination of two of the following methods:&#xD;
  &#xD;
            -  Condoms (male or female) with or without a spermicidal agent.&#xD;
  &#xD;
            -  Diaphragm or cervical cap with spermicide.&#xD;
  &#xD;
            -  Intrauterine device (IUD).&#xD;
  &#xD;
            -  Hormonal-based contraception. Subjects who are not of reproductive potential (women&#xD;
               who are premenarche or have been post-menopausal for at least 24 consecutive months or&#xD;
               have undergone hysterectomy, tubal ligation, salpingectomy, and/or bilateral&#xD;
               oophorectomy or men who have documented azoospermia) are eligible without requiring&#xD;
               the use of contraception.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Binod Dhakal, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Medical College of Wisconsin</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Medical College of Wisconsin Cancer Center Clinical Trials Office</last_name>
      <phone>866-680-0505</phone>
      <phone_ext>8900</phone_ext>
      <email>cccto@mcw.edu</email>
    </overall_contact>
    <reference>
      <citation>Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25.</citation>
      <PMID>30592986</PMID>
    </reference>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>July 28, 2023</study_first_submitted>
    <study_first_submitted_qc>July 28, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 4, 2023</study_first_posted>
    <last_update_submitted>September 14, 2023</last_update_submitted>
    <last_update_submitted_qc>September 14, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 15, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
      <investigator_full_name>Binod Dhakal</investigator_full_name>
      <investigator_title>Associate Professor</investigator_title>
    </responsible_party>
    <keyword>CAR-T</keyword>
    <keyword>Chimeric antigen receptor T-cell therapy</keyword>
    <keyword>CAR Therapy</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Multiple Myeloma</mesh_term>
      <mesh_term>Neoplasms, Plasma Cell</mesh_term>
    </condition_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/NCT05976555
  org study id: IIT-DHAKAL-TGF-BETA-BCMA
  nct id: NCT05976555
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: No
  This is a phase I, interventional, single-arm, open-label, dose-finding treatment study
        designed to evaluate the safety and efficacy of interleukin-7(IL-7) / interleukin-15 (IL-15)
        manufactured CAR T cells in adult patients with relapsed and/or refractory myeloma that have
        failed prior therapies.
  BCMA-Transforming growth factor-beta (TGFβ) CAR-T cells will be administered either fresh or
        thawed after cryopreservation by IV injection. Patients will receive one of three dose levels
        of BCMA-TGFβ CAR-T cells based on our dose escalation design.
  
        After the maximal tolerated dose (MTD) is determined, an additional dose-expansion cohort of
        up to 9 patients (3 BCMA-naïve and 6 BCMA exposed) may be enrolled at that dose to further
        describe the safety and preliminary efficacy of that dose.
  allocation: Non-Randomized
  intervention model: Sequential Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Number of Adverse Events After BCMA-TGFβ CAR-T Cell Infusion
  time frame: from infusion until Day +28 post CAR T infusion
  description: Incidence of adverse events with grade 3 to 5 severity using NCI CTCAE version 5.0 and the Lee et al. consensus manuscript (which outlines the defining characteristics of each grade for cytokine release syndrome; please refer to the reference below).
  arm group label: BCMA-TGFβ CAR-T cells (0.75 x10^6 cells/kg)
  arm group type: Experimental
  description: BCMA-TGFβ CAR-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Subjects will receive one of three dose levels of BCMA-TGFβ CAR-T cells based on the dose escalation design.
  arm group label: BCMA-TGFβ CAR-T cells (1 x 10^6 cells/kg)
  arm group type: Experimental
  description: BCMA-TGFβ CAR-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Subjects will receive one of three dose levels of BCMA-TGFβ CAR-T cells based on the dose escalation design.
  arm group label: BCMA-TGFβ CAR-T cells (2.5 x 10^6 cells/kg)
  arm group type: Experimental
  description: BCMA-TGFβ CAR-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Subjects will receive one of three dose levels of BCMA-TGFβ CAR-T cells based on the dose escalation design.
  arm group label: BCMA-TGFβ CAR-T cells (Maximum tolerated dose)
  arm group type: Experimental
  description: After the maximal tolerated dose (MTD) is determined, an additional dose-expansion cohort of up to 9 patients (3 BCMA-naïve and 6 BCMA exposed) may be enrolled at that dose.
  intervention type: Biological
  intervention name: BCMA-TGFβ CAR-T cells (0.75 x10^6 cells/kg)
  description: This is dose level -1.
  arm group label: BCMA-TGFβ CAR-T cells (0.75 x10^6 cells/kg)
  arm group label: BCMA-TGFβ CAR-T cells (Maximum tolerated dose)
  intervention type: Biological
  intervention name: BCMA-TGFβ CAR-T cells (1 x 10^6 cells/kg)
  description: This is the starting dose (dose level 0).
  arm group label: BCMA-TGFβ CAR-T cells (1 x 10^6 cells/kg)
  arm group label: BCMA-TGFβ CAR-T cells (Maximum tolerated dose)
  intervention type: Biological
  intervention name: BCMA-TGFβ CAR-T cells (2.5 x 10^6 cells/kg)
  description: This is dose level 1.
  arm group label: BCMA-TGFβ CAR-T cells (2.5 x 10^6 cells/kg)
  arm group label: BCMA-TGFβ CAR-T cells (Maximum tolerated dose)
  intervention type: Biological
  intervention name: Maximum tolerated dose
  description: The maximum tolerated dose is yet to be determined.
  arm group label: BCMA-TGFβ CAR-T cells (Maximum tolerated dose)
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 80 Years
  healthy volunteers: No
  last name: Binod Dhakal, MD
  role: Principal Investigator
  affiliation: Medical College of Wisconsin
  last name: Medical College of Wisconsin Cancer Center Clinical Trials Office
  phone: 866-680-0505
  phone ext: 8900
  email: cccto@mcw.edu
  citation: Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25.
  PMID: 30592986
  responsible party type: Principal Investigator
  investigator affiliation: Medical College of Wisconsin
  investigator full name: Binod Dhakal
  investigator title: Associate Professor
  mesh term: Multiple Myeloma
  mesh term: Neoplasms, Plasma Cell
  sharing ipd: No