<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/NCT03766126</url>
  </required_header>
  <id_info>
    <org_study_id>831619 (UPCC 35418)</org_study_id>
    <nct_id>NCT03766126</nct_id>
  </id_info>
  <brief_title>Lentivirally Redirected CD123 Autologous T Cells in AML</brief_title>
  <official_title>Phase 1 Study of Lentivirally Transduced T Cells Engineered to Contain Anti-CD123 Linked to TCRζ and 4-1BB Signaling Domains in Subjects With Refractory or Relapsed Acute Myeloid Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pennsylvania</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>
      Phase 1 open-label study to estimate the safety, manufacturing feasibility, and efficacy of&#xD;
      intravenously administered, lentivirally transduced T cells expressing anti-CD123 chimeric&#xD;
      antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ /4-1BB) costimulatory domains in&#xD;
      Acute Myeloid Leukemia (AML) subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase 1 study to determine the safety, feasibility, and efficacy of CART123 cells&#xD;
      following lymphodepleting chemotherapy in patients with relapsed/refractory AML. Subjects&#xD;
      will be treated with a split dosing approach of CART123 cells (10% Day 0; 30% Day 1; 60% Day&#xD;
      2) for Cohort 1a/1b or a single IV administration of CART123 cells for Cohort 2.&#xD;
&#xD;
      The total dose administered to each subject will be based on body weight obtained at the time&#xD;
      of apheresis. Thus, the target total transduced dose, preceded by lymphodepleting&#xD;
      chemotherapy, is 1-2x10^6 CART123 cells/kg for Cohort 1a, 5x10^6 CART123 cells/kg for Cohort&#xD;
      1b, or 2x10^6 CART-123 cells/kg for Cohort 2. The protocol-specified minimum acceptable dose&#xD;
      for infusion is 1x10^5 CART123 cells/kg for all cohorts.&#xD;
&#xD;
      It is recommended per routine clinical care, that all subjects with marrow aplasia at Day&#xD;
      28+/-5 undergo allogeneic hematopoietic cell transplantation (alloHCT) as a rescue strategy.&#xD;
      If required, this procedure will be performed as part of routine care, outside of the scope&#xD;
      of this research study, however subjects will continue to be followed on study. All subjects&#xD;
      should therefore have a previously identified stem cell donor in order to participate in this&#xD;
      study. Please see Section 6.8 for additional details.&#xD;
&#xD;
      All subjects will be followed monthly for up to 6 months post the first CART123 cell infusion&#xD;
      (Day 0). Thereafter subjects will be transitioned into LTFU for up to 15 years post infusion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 6, 2018</start_date>
  <completion_date type="Anticipated">December 3, 2033</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety profile of CART123 cells by monitoring the frequency and severity of adverse events assessed by the National Cancer Institute (NCI) - Common Toxicity Criteria (v5.0)</measure>
    <time_frame>5 years</time_frame>
    <description>Assess the safety of CART123 cells in AML subjects following lymphodepletion with cyclophosphamide + fludarabine.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluate the percentage of manufacturing products that do not meet release criteria for vector transduction efficiency, T cell product purity, viability, sterility.</measure>
    <time_frame>5 year</time_frame>
    <description>Evaluate the percentage of manufacturing products that do not meet release criteria for vector transduction efficiency, T cell product purity, viability, sterility.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Estimation of CART123 efficacy by evaluation of OS and PFS of subjects at protocol defined intervals which receive at least one infusion of CART123 cells</measure>
    <time_frame>15 years</time_frame>
    <description>Estimate the efficacy of at least 1 dose of CART123 cells in AML subjects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) as percent of subjects surviving at protocol defined time points.</measure>
    <time_frame>15 years</time_frame>
    <description>Overall survival (OS) and progression-free survival (PFS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) as percent of subjects surviving without disease progression at protocol defined time points</measure>
    <time_frame>15 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>15 years</time_frame>
    <description>Duration of response (DOR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Necessity of rescue bone marrow transplant</measure>
    <time_frame>15 years</time_frame>
    <description>Need for rescue allogeneic hematopoietic cell transplantation (alloHCT)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Acute Myeloid Leukemia, in Relapse</condition>
  <condition>Acute Myeloid Leukemia, Adult</condition>
  <condition>Acute Myeloid Leukemia, Refractory</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CART123 cells; cyclophosphamide; fludarabine</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CART123 cells; cyclophosphamide; fludarabine</intervention_name>
    <description>CART123 cells following lymphodepleting chemotherapy in patients with relapsed/refractory AML. Subjects will be treated with a split dosing approach of CART123 cells (10% Day 0; 30% Day 1; 60% Day 2) for Cohort 1a/1b or a single IV administration of CART123 cells for Cohort 2.&#xD;
The total dose administered to each subject will be based on body weight obtained at the time of apheresis. Thus, the target total transduced dose, preceded by lymphodepleting chemotherapy, is 1-2x10^6 CART123 cells/kg for Cohort 1a, 5x10^6 CART123 cells/kg for Cohort 1b, or 2x10^6 CART-123 cells/kg for Cohort 2. The protocol-specified minimum acceptable dose for infusion is 1x10^5 CART123 cells/kg.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
    <other_name>T Cells Containing Anti-CD123 Signaling Domains</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female subjects 18 years of age or older&#xD;
&#xD;
          2. Subjects with active acute myeloid leukemia (AML) with no available curative treatment&#xD;
             options using currently available therapies. Specifically:&#xD;
&#xD;
               1. AML that has not achieved a complete remission or morphologic leukemia free state&#xD;
                  by ELN criteria (Döhner et al., 2017 Blood, 129(4):424-447); partial remission or&#xD;
                  refractory disease (including primary refractory) are eligible. Or:&#xD;
&#xD;
               2. AML relapsed following allogeneic stem cell transplantation (including MDS&#xD;
                  evolved to AML post-allogeneic stem cell transplantation). Note: morphologic&#xD;
                  relapse is not required; persistent/recurrent disease-associated molecular,&#xD;
                  phenotypic or cytogenetic abnormalities (measurable residual disease, MRD) at any&#xD;
                  time after allogeneic HCT is eligible&#xD;
&#xD;
          3. Subjects with relapsed disease after prior transplant must meet one of the following:&#xD;
&#xD;
             a. Subjects with relapsed disease after prior allogeneic HCT (myeloablative or&#xD;
             non-myeloablative) will be eligible if they meet all other inclusion criteria and i.&#xD;
             Have no residual donor cells (by STR analysis on 2 occasions separated by at least 1&#xD;
             month), OR: ii. Donor cells are present but there is no active GVHD (&gt;Gr II), subject&#xD;
             does not require systemic immunosuppression and is more than 3 months from transplant,&#xD;
             and at least 1 month off GVHD prophylaxis.&#xD;
&#xD;
             b. Subjects with relapsed disease after prior autologous or syngeneic HCT will be&#xD;
             eligible if they meet all other inclusion criteria and it has been more than 3 months&#xD;
             from transplant.&#xD;
&#xD;
          4. Subjects must have a suitable stem cell donor available who may donate cells in the&#xD;
             event the subject needs to undergo an allogeneic HCT. Donor may be matched or&#xD;
             mismatched and must be found to be suitable according to the institution's standard&#xD;
             criteria; donors must be fully cleared to proceed as the donor.&#xD;
&#xD;
          5. Satisfactory organ functions:&#xD;
&#xD;
               1. Creatinine ≤ 1.6 mg/dl&#xD;
&#xD;
               2. ALT/AST must be ≤5 x upper limit of normal unless related to disease&#xD;
&#xD;
               3. Direct bilirubin or total bilirubin &lt; 2.0mg/dl, unless subject has Gilbert's&#xD;
                  syndrome (≤3.0 mg/dL);&#xD;
&#xD;
               4. Left ventricular ejection fraction ≥ 40% as confirmed by ECHO/MUGA&#xD;
&#xD;
          6. ECOG Performance status 0-2.&#xD;
&#xD;
          7. Written informed consent is given.&#xD;
&#xD;
          8. No contraindications for leukapheresis.&#xD;
&#xD;
          9. Subjects of reproductive potential must agree to use acceptable birth control methods&#xD;
             (as described in protocol Section 4.3).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant or lactating (nursing women) women.&#xD;
&#xD;
          2. Patients with relapsed AML with t(15:17).&#xD;
&#xD;
          3. HIV infection.&#xD;
&#xD;
          4. Active hepatitis B or hepatitis C infection.&#xD;
&#xD;
          5. Concurrent use of systemic steroids or immunosuppressant medications. Recent or&#xD;
             current use of inhaled steroids or physiologic replacement with hydrocortisone is not&#xD;
             exclusionary. For additional details regarding use of steroids while on study, please&#xD;
             see Section 5.5.&#xD;
&#xD;
          6. Any uncontrolled active medical disorder that would preclude participation as&#xD;
             outlined.&#xD;
&#xD;
          7. Subjects with signs or symptoms indicative of CNS involvement. A CNS evaluation should&#xD;
             be performed as clinically appropriate to rule out CNS involvement.&#xD;
&#xD;
          8. Known history of allergy or hypersensitivity to study product excipients (human serum&#xD;
             albumin, DMSO, and Dextran 40).&#xD;
&#xD;
          9. Class III/IV cardiovascular disability according to the New York Heart Association&#xD;
             Classification (see Appendix 3).&#xD;
&#xD;
         10. Patients with a known history or prior diagnosis of optic neuritis or other&#xD;
             immunologic or inflammatory disease affecting the central nervous system, and&#xD;
             unrelated to leukemia or previous leukemia treatment.&#xD;
&#xD;
         11. Subjects with clinically apparent arrhythmia, or arrhythmias that are not stable on&#xD;
             medical management, within 2 weeks of the Screening/Enrollment visit.&#xD;
&#xD;
         12. Patients with any prior history of myeloproliferative neoplasm.&#xD;
&#xD;
         13. Patients with the JAK2 V617F mutation by PCR or next generation sequencing.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 4, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 6, 2018</study_first_posted>
  <last_update_submitted>August 17, 2023</last_update_submitted>
  <last_update_submitted_qc>August 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>refractory</keyword>
  <keyword>relapsed</keyword>
  <keyword>Acute</keyword>
  <keyword>Myeloid</keyword>
  <keyword>leukemia</keyword>
  <keyword>AML</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03766126
org study id: 831619 (UPCC 35418)
nct id: NCT03766126
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Phase 1 open-label study to estimate the safety, manufacturing feasibility, and efficacy of
      intravenously administered, lentivirally transduced T cells expressing anti-CD123 chimeric
      antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ /4-1BB) costimulatory domains in
      Acute Myeloid Leukemia (AML) subjects.
This is a Phase 1 study to determine the safety, feasibility, and efficacy of CART123 cells
      following lymphodepleting chemotherapy in patients with relapsed/refractory AML. Subjects
      will be treated with a split dosing approach of CART123 cells (10% Day 0; 30% Day 1; 60% Day
      2) for Cohort 1a/1b or a single IV administration of CART123 cells for Cohort 2.

      The total dose administered to each subject will be based on body weight obtained at the time
      of apheresis. Thus, the target total transduced dose, preceded by lymphodepleting
      chemotherapy, is 1-2x10^6 CART123 cells/kg for Cohort 1a, 5x10^6 CART123 cells/kg for Cohort
      1b, or 2x10^6 CART-123 cells/kg for Cohort 2. The protocol-specified minimum acceptable dose
      for infusion is 1x10^5 CART123 cells/kg for all cohorts.

      It is recommended per routine clinical care, that all subjects with marrow aplasia at Day
      28+/-5 undergo allogeneic hematopoietic cell transplantation (alloHCT) as a rescue strategy.
      If required, this procedure will be performed as part of routine care, outside of the scope
      of this research study, however subjects will continue to be followed on study. All subjects
      should therefore have a previously identified stem cell donor in order to participate in this
      study. Please see Section 6.8 for additional details.

      All subjects will be followed monthly for up to 6 months post the first CART123 cell infusion
      (Day 0). Thereafter subjects will be transitioned into LTFU for up to 15 years post infusion.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety profile of CART123 cells by monitoring the frequency and severity of adverse events assessed by the National Cancer Institute (NCI) - Common Toxicity Criteria (v5.0)
time frame: 5 years
description: Assess the safety of CART123 cells in AML subjects following lymphodepletion with cyclophosphamide + fludarabine.
measure: Evaluate the percentage of manufacturing products that do not meet release criteria for vector transduction efficiency, T cell product purity, viability, sterility.
time frame: 5 year
description: Evaluate the percentage of manufacturing products that do not meet release criteria for vector transduction efficiency, T cell product purity, viability, sterility.
measure: Estimation of CART123 efficacy by evaluation of OS and PFS of subjects at protocol defined intervals which receive at least one infusion of CART123 cells
time frame: 15 years
description: Estimate the efficacy of at least 1 dose of CART123 cells in AML subjects
measure: Overall Survival (OS) as percent of subjects surviving at protocol defined time points.
time frame: 15 years
description: Overall survival (OS) and progression-free survival (PFS)
measure: Progression-free survival (PFS) as percent of subjects surviving without disease progression at protocol defined time points
time frame: 15 years
measure: Duration of response (DOR)
time frame: 15 years
description: Duration of response (DOR)
measure: Necessity of rescue bone marrow transplant
time frame: 15 years
description: Need for rescue allogeneic hematopoietic cell transplantation (alloHCT)
arm group label: Treatment Arm
arm group type: Experimental
description: CART123 cells; cyclophosphamide; fludarabine
intervention type: Biological
intervention name: CART123 cells; cyclophosphamide; fludarabine
description: CART123 cells following lymphodepleting chemotherapy in patients with relapsed/refractory AML. Subjects will be treated with a split dosing approach of CART123 cells (10% Day 0; 30% Day 1; 60% Day 2) for Cohort 1a/1b or a single IV administration of CART123 cells for Cohort 2.
The total dose administered to each subject will be based on body weight obtained at the time of apheresis. Thus, the target total transduced dose, preceded by lymphodepleting chemotherapy, is 1-2x10^6 CART123 cells/kg for Cohort 1a, 5x10^6 CART123 cells/kg for Cohort 1b, or 2x10^6 CART-123 cells/kg for Cohort 2. The protocol-specified minimum acceptable dose for infusion is 1x10^5 CART123 cells/kg.
arm group label: Treatment Arm
other name: T Cells Containing Anti-CD123 Signaling Domains
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Cyclophosphamide
mesh term: Fludarabine
sharing ipd: No