<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/NCT03829540</url>
  </required_header>
  <id_info>
    <org_study_id>CTO-IUSCCC-ICG122-101</org_study_id>
    <secondary_id>FD-R-006820-01</secondary_id>
    <nct_id>NCT03829540</nct_id>
  </id_info>
  <brief_title>CD4CAR for CD4+ Leukemia and Lymphoma</brief_title>
  <official_title>A Phase I, Multicenter Study of CD4- Directed Chimeric Antigen Receptor Engineered T-cells (CD4CAR) in Patients With Relapsed or Refractory CD4+ Hematological Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Huda Salman</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>iCell Gene Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Indiana University</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 study is designed as a single arm open label Phase I, 3x3, multicenter study of&#xD;
      CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in patients with relapsed&#xD;
      or refractory T-cell leukemia and lymphoma. Specifically, the study will evaluate the safety&#xD;
      and feasibility of CD4CAR T-cells. Funding Source - FDA OOPD&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be performed as a dose-escalation protocol. Due to the relatively low&#xD;
      incidence and prevalence of cluster of differentiation 4-positive (CD4+) hematological&#xD;
      malignancies and the associated aggressive nature of these diseases and the sequel of&#xD;
      treatment failure, the investigators expect to recruit 20 subjects at Stony Brook, Indiana&#xD;
      University, and other identified sites with an expected dropout rate of 25% primarily due to&#xD;
      rapid progression or death and screen and or manufacturing failure. Taking this into account,&#xD;
      the investigators expect to treat 15 patients. The study will utilize autologous CD4CAR&#xD;
      T-cells that are engineered to express a chimeric antigen receptor (CAR) targeting CD4 that&#xD;
      is linked to the cluster of differentiation 28 (CD28), 4-1BB, cluster of differentiation&#xD;
      3-zeta (CD3ζ) signaling chains (third generation CAR).&#xD;
&#xD;
      At entry, disease status will be staged and investigators will determine if the subject has&#xD;
      adequate T cell number for apheresis and for manufacturing CD4CAR cells. Qualifying subjects&#xD;
      will be leukapheresed to obtain large numbers of peripheral blood mononuclear cells (PBMC)&#xD;
      for the manufacturing. Next, participants will receive conditioning chemotherapy. If tumor&#xD;
      burden is sufficiently reduced (screening step), participants will receive CD4CAR cells by&#xD;
      infusion on Day 0 of treatment.&#xD;
&#xD;
      For cell harvest, 12-15-liter apheresis procedure will be performed at the apheresis center&#xD;
      with the intention to harvest at least 50x10^9-nucleated cells to manufacture CD4CAR T-cells.&#xD;
      A portion of the pheresed cells will also be cryopreserved for FDA look-back requirements and&#xD;
      for further research. The T-cells will be purified from the PBMC, transduced with CD4CAR&#xD;
      lentiviral vector, expanded in vitro, and then frozen for administration. Each dose will be&#xD;
      stored in either one or two bags. The route of administration is by IV infusion and the&#xD;
      duration of infusion will be approximately 20 minutes. Each bag will contain an aliquot&#xD;
      (30-50 mL) of liquid suitable for freezing, and containing the following infusible grade&#xD;
      reagents (% v/v): 62.5cc Plasmalyte-A 5% dextrose; 7.5cc Pure dimethylsulfoxide (DMSO), 20cc&#xD;
      of 25% Human Serum Albumin, and 10cc Dextran 40. The cell product is expected to be ready for&#xD;
      release approximately 3-4 weeks after apheresis.&#xD;
&#xD;
      If the disease progresses during the manufacturing period participants may be excluded from&#xD;
      the study. Minimal chemotherapy to keep the disease under control in the meanwhile is allowed&#xD;
      if deemed necessary by investigators.&#xD;
&#xD;
      A single dose of CD4CAR transduced T cells will consist of the cell number for the dose level&#xD;
      to be infused.&#xD;
&#xD;
      Post-infusion monitoring of CD4CAR T-cells: Subjects will have blood drawn for cytokine&#xD;
      levels, CD4CAR Transgene Copy Number (PCR) and flow cytometry in order to evaluate the&#xD;
      presence of CD4CAR cells on days 0, 1, 3, 5, 7, 14, 28, and 42 following infusion (or as&#xD;
      clinically needed). Cytokines levels will be evaluated per schedule above in addition to and&#xD;
      as needed every 8 +/- 2 hours as feasible if/when CRS occurs and until resolution. Active&#xD;
      monitoring of fungal and viral infections during treatment while utilizing standard&#xD;
      prophylaxis recommended for HIV-positive patients with T-cell aplasia and those undergoing&#xD;
      allogeneic stem cell transplant. Investigators plan to collect data about clinicoradiologic&#xD;
      measurements of residual tumor burden starting on day 6 and weekly afterward until day 42 and&#xD;
      then monthly for 6 months. This will be followed by quarterly clinical evaluations for the&#xD;
      next two (2) years with a medical history, physical examination, and comprehensive blood&#xD;
      testing. After these short- and intermediate-term evaluations are performed, these patients&#xD;
      will enter a rollover study to assess for disease-free survival (DFS), relapse, and the&#xD;
      development of other health problems or malignancies where follow-up will be up tp twice a&#xD;
      year by phone and a questionnaire for an additional thirteen (13) years. The treating&#xD;
      physician will decide to proceed with allogeneic or autologous transplant when needed.&#xD;
&#xD;
      Dose of CD4CAR description: the main objective of this study is to establish a recommended&#xD;
      dose and/or schedule of CD4CAR. The guiding principle for dose escalation in phase I is to&#xD;
      avoid unnecessary exposure of patients to sub-therapeutic doses (i.e., to treat as many&#xD;
      patients as possible within the therapeutic dose range) while preserving safety and&#xD;
      maintaining rapid accrual. Investigators will use the rule-based traditional Phase I &quot;3+3&quot;&#xD;
      design for the evaluation of safety. Based on lab experience in mice the starting dose (dose&#xD;
      level 1) for the first cohort of three patients in phase I portion of the study will be&#xD;
      8x10^5 cells. The dose escalation or de-escalation will follow a modified Fibonacci sequence&#xD;
      as below.&#xD;
&#xD;
      If more than one patient out of the first cohort of three patients in dose level 1 experience&#xD;
      dose limiting toxicity (DLT), the trial will be placed on hold. If zero or one out of three&#xD;
      patients in the first cohort of dose level 1 experience DLT, three more patients will be&#xD;
      enrolled at dose level 1; the dose escalation continues until at least two patients among a&#xD;
      cohort of six patients experience DLT (i.e., ≥33% of patients with a DLT at this dose level)&#xD;
&#xD;
        -  If one of the first three patients in dose level 1 experiences a DLT, three more&#xD;
           patients will be treated at dose level 1.&#xD;
&#xD;
        -  If none of the three patients or only one of the 6 patients in the dose level 1&#xD;
           experiences a DLT, the dose escalation continues to the dose level 2&#xD;
&#xD;
        -  If one of the first three patients in dose level 2 experience a DLT, three more patients&#xD;
           will be treated at dose level 2&#xD;
&#xD;
        -  If none of the three patients or only one of the 6 patients in the dose level2&#xD;
           experiences a DLT, the dose escalation continues to the dose level 3&#xD;
&#xD;
        -  If one of the first three patients in dose level 3 experiences a DLT, three more&#xD;
           patients will be treated at dose level 3&#xD;
&#xD;
        -  If none of the three patients or only one of the 6 patients in the dose level 3&#xD;
           experiences a DLT, dose level 3 will be declared the maximum tolerated dose (MTD) and&#xD;
           will be used as the recommended phase II dose (RP2D) for the phase II portion of the&#xD;
           study.&#xD;
&#xD;
      In summary, the dose escalation continues until at least two patients among a cohort of six&#xD;
      patients experience DLT (i.e., ≥33% of patients with a DLT at that dose level). The&#xD;
      recommended dose for phase II trials is defined as one dose level below this toxic dose&#xD;
      level. Since some grade 3 and possibly 4 toxicities are highly likely to be reversible, grade&#xD;
      3 infectious, hematological and vascular toxicities will not be considered DLTs mandating&#xD;
      dose reduction. Also allergic or infusion-related reactions ≤ grade 3 will not be counted as&#xD;
      DLTs. There will be no intra-patient dose escalation or reduction.&#xD;
&#xD;
      To allow for full spectrum toxicity duration evaluation and reporting, no patients within the&#xD;
      same or a different cohort will be initiated on lymphodepleting chemotherapy sooner than 42&#xD;
      days from the initiation date of the preceding patient.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 18, 2019</start_date>
  <completion_date type="Anticipated">December 2037</completion_date>
  <primary_completion_date type="Anticipated">December 2025</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>Number of participants with treatment-related adverse events as assessed by CTCAE v5.0</measure>
    <time_frame>18-24 months</time_frame>
    <description>To assess the safety and feasibility of the chimeric antigen receptor T cells transduced with the anti-CD4 lentiviral vector (referred to as &quot;CD4CAR&quot; cells) according to CTCAE grading. The feasibility of treating those adverse events and their duration till resolution will also be described.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of in vivo survival of the CD4CAR.</measure>
    <time_frame>18-24 months</time_frame>
    <description>Persistence of CD4CAR will be monitored by measuring the CD4CAR transgene copy number at variable time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of manufacturing failure</measure>
    <time_frame>18-24 months</time_frame>
    <description>The number of failed manufacturing attempts of CD4 CAR, per subject and overall, in this patient population. Manufacturing failure is defined as failure to manufacture the adequate CD4CAR cell dose for the particular cohort the patient is enrolled on. Three manufacturing attempts per patient are allowed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response</measure>
    <time_frame>18-24 months</time_frame>
    <description>Clinical response to T-cell infusion will be evaluated by comparing disease before and after infusion identified by:&#xD;
standard imaging (PET CT or PET MRI) for lymphoma patients&#xD;
bone marrow biopsy for leukemia patients&#xD;
peripheral blood cells morphology, flow cytometry panel, immunohistochemistry, and other blood molecular markers for both lymphoma and leukemia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trafficking of CD4CAR at tumor sites and at sites with significant toxicity</measure>
    <time_frame>18-24 months</time_frame>
    <description>Quantification of both of CD4CAR by flowcytometry and transgene copy number by polymerase chain reaction (PCR) will be measured at tumor sites in bone marrow and lymph nodes at variable time points if applicable. Same tests will be done on biopsies of organs that shows significant toxicity if need be.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with immune reactions against CD4CAR</measure>
    <time_frame>18-24 months</time_frame>
    <description>The absolute and relative number of subjects who develop immune reactions against the treatment over a period of 2 years. Human anti-mouse antibody (HAMA) ELISA tests will be carried out in the blood of participants at multiple times after initial treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum cytokines levels</measure>
    <time_frame>18-24 months</time_frame>
    <description>Serum cytokine levels will be evaluated on Day 2, 4, 7, 11, 14, 21, 28 in addition to planned monitoring during CRS every 8 hours and until resolution. These cytokines include interleukin-6 (IL-6), interferon-γ, tumor necrosis factor, IL-2, IL-2-receptor-a, IL-8, and IL-10</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine CD4CAR cell subsets during proliferation</measure>
    <time_frame>18-24 months</time_frame>
    <description>Participants' blood will be tested by flow cytometry to determine the relative abundance of cellular subsets that may result from CD4CAR T cells upon their proliferation. These subsets include Tcm, Tem, and Tregs.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>T-cell Lymphoma</condition>
  <condition>T-cell Leukemia</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Redirected autologous T cells transduced with the anti-CD4 lentiviral vector (referred to as &quot;CD4CAR&quot; cells)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CD4CAR</intervention_name>
    <description>CD4CAR cells transduced with a lentiviral vector to express the single-chain variable fragment (scFv) nucleotide sequence of the anti-CD4 molecule derived from humanized monoclonal ibalizumab and the intracellular domains of CD28 and 4-1BB co-activators fused to the CD3ζ T-cell activation signaling domain administered by IV infusions as a single dose</description>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
        In order to be eligible to participate in this study, an individual will be enrolled if&#xD;
        they meet the following criteria:&#xD;
&#xD;
          1. Patients must voluntarily sign and date informed consent forms that state his or her&#xD;
             willingness to comply with all study procedures and availability for the duration of&#xD;
             the study.&#xD;
&#xD;
          2. Age 18 years old or older&#xD;
&#xD;
          3. Subjects with documented CD4+ hematologic malignancies. Male and female subjects with&#xD;
             CD4+ T-cell malignancies with either relapsed or refractory disease (including those&#xD;
             patients who have undergone a prior transplant and patients with an inadequate&#xD;
             response after 4-6 cycles of standard chemotherapy)&#xD;
&#xD;
          4. For patients who present with CD4+ Leukemia, either relapsed disease or minimal&#xD;
             residual disease (MRD); any of the following are eligible:&#xD;
&#xD;
               1. Peripheral T-cell leukemia, NOS&#xD;
&#xD;
               2. T-cell prolymphocytic leukemia&#xD;
&#xD;
               3. Adult T-cell leukemia&#xD;
&#xD;
               4. T-cell large granular lymphocytic leukemia&#xD;
&#xD;
               5. T cell acute lymphoblastic leukemia T-ALL&#xD;
&#xD;
          5. For patients with CD4+ Lymphoma, either relapsed or refractory disease; any of the&#xD;
             following are eligible:&#xD;
&#xD;
               1. Peripheral T-cell lymphoma, NOS&#xD;
&#xD;
               2. Sezary syndrome/cutaneous T-cell lymphoma&#xD;
&#xD;
               3. Angioimmunoblastic T-cell lymphoma&#xD;
&#xD;
               4. Adult T-cell lymphoma&#xD;
&#xD;
               5. Blastic plasmacytoid dendritic cell neoplasm (BPDCN)&#xD;
&#xD;
          6. Creatinine clearance of &gt; 60 ml/min (or otherwise non clinically-significant, per&#xD;
             study investigator)&#xD;
&#xD;
          7. ALT/AST &lt; 3 x ULN&#xD;
&#xD;
          8. Bilirubin &lt; 2 x ULN&#xD;
&#xD;
          9. Pulmonary Function Test (PFT) with a DLCO of ≥ 60%.&#xD;
&#xD;
         10. Adequate echocardiogram with EF of ≥50%&#xD;
&#xD;
         11. Adequate venous access for apheresis and no other contraindications for leukapheresis&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Pregnant or lactating women. The safety of this therapy on unborn children is not&#xD;
             known. Female study participants of reproductive potential (see definition below) must&#xD;
             have a negative serum or urine pregnancy test prior to initiation of conditioning&#xD;
             chemotherapy, per research sites' clinical policy.&#xD;
&#xD;
          2. Uncontrolled active infection necessitating systemic therapy.&#xD;
&#xD;
          3. Active hepatitis B or hepatitis C infection. Active hepatitis C is defined as the&#xD;
             hepatitis C antibody is positive while quantitative HCV RNA results exceed the lower&#xD;
             detection limit.&#xD;
&#xD;
             Note the following subjects will be eligible:&#xD;
&#xD;
               -  Subjects with a history of hepatitis B but have received antiviral therapy and&#xD;
                  have non-detectable viral DNA for 6 months prior to enrollment are eligible&#xD;
&#xD;
               -  Subjects seropositive for HBS antibodies due to hepatitis B virus vaccine with no&#xD;
                  signs or active infection (Negative HBs Ag, HBc and HBe Ags) are eligible&#xD;
&#xD;
               -  Subjects who had hepatitis C but have received antiviral therapy and show no&#xD;
                  detectable hepatitis C virus (HCV) viral RNA for 6 months are eligible&#xD;
&#xD;
               -  If hepatitis C antibody test is positive, then patients must be tested for the&#xD;
                  presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR)&#xD;
                  and be hepatitis C virus ribonucleic acid (HCV RNA) negative.&#xD;
&#xD;
          4. Concurrent use of systemic glucocorticoids in greater than replacement doses (unless&#xD;
             as a part of a standard of care salvage therapy or conditioning protocol), or steroid&#xD;
             dependency defined in rheumatological and pulmonary diseases as uninterrupted&#xD;
             corticosteroid intake for more than a year at a dosage of 0.3 mg/kg/day or greater,&#xD;
             and where the underlying disease worsens on temporary stoppage of steroid therapy,&#xD;
             with symptoms of steroids withdrawal (eg, lethargy, headache, weakness,&#xD;
             pseudorheumatism, emotional disturbances, etc) precipitated by the temporary stoppage.&#xD;
&#xD;
             Subjects who receive daily corticosteroids in replacement doses can be included in the&#xD;
             study. The replacement doses are defined as following:&#xD;
&#xD;
               1. Hydrocortisone 25mg/day or less&#xD;
&#xD;
               2. Prednisone 10mg/day or less&#xD;
&#xD;
               3. Dexamethasone 4mg or less Note: Recent or current use of inhaled glucocorticoids&#xD;
                  is not exclusionary, as this route pertains extremely minimal systemic&#xD;
                  penetration.&#xD;
&#xD;
          5. Any previous treatment with any gene therapy products.&#xD;
&#xD;
          6. Any uncontrolled active medical disorder that would preclude participation as outlined&#xD;
             in the opinion of the treating investigator and/or study chair&#xD;
&#xD;
          7. HIV infection.&#xD;
&#xD;
          8. Patients declining to consent for treatment&#xD;
&#xD;
          9. Subjects who have received or will receive live vaccines within 30 days before the&#xD;
             first experimental cell treatment. Inactivated seasonal flu vaccination is allowed.&#xD;
&#xD;
         10. Subjects with active autoimmune diseases who need systematic treatments (such as&#xD;
             disease modifying agents, corticosteroids and immunosuppressive drugs) in the last 2&#xD;
             years.&#xD;
&#xD;
             Note: Replacement therapy (thyroxine, insulin or physiological corticosteroid&#xD;
             replacement therapy (up to10 mg of oral daily prednisone or equivalent in&#xD;
             hydrocortisone and dexamethasone) to treat adrenal dysfunction or pituitary&#xD;
             dysfunction) is not considered as systematic therapy. Subjects who need inhalation&#xD;
             corticosteroid therapy can be included in this trial. Subjects with vitiligo or in&#xD;
             long-term remission of pediatric asthma or allergic diseases can be included in this&#xD;
             trial.&#xD;
&#xD;
         11. Subjects with a history of mental disorders or drug abuse that may influence treatment&#xD;
             compliance.&#xD;
&#xD;
         12. Active malignancy not related to a T-cell malignancy that has required therapy in the&#xD;
             last 3 years or is not in complete remission. Exceptions to this criterion include&#xD;
             successfully treated non-metastatic basal cell or squamous cell skin carcinoma, or&#xD;
             prostate cancer that does not require therapy. Other similar malignant conditions may&#xD;
             be discussed with and permitted by the Principal Investigator.&#xD;
&#xD;
        Screen Failure&#xD;
&#xD;
        Subjects who fail to cytoreduce with conditioning chemotherapy with persistence of high&#xD;
        disease burden will be considered a screenfail according to the guidelines below:&#xD;
&#xD;
          1. CD4+ Leukemias ( Liquid Blood and marrow disease):&#xD;
&#xD;
               1. Subjects at study entry with bone marrow malignant replacement estimated at &gt; 80%&#xD;
                  of total cellularity and accompanied by significant peripheral pancytopenia, ANC&#xD;
                  &lt;500, platelet count &lt; 50,000 will need to have roughly 50% or greater reduction&#xD;
                  on the marrow malignant component to be considered eligible after cytoreductive&#xD;
                  chemotherapy and for CD4CAR infusion. This will be determined and approved by PI,&#xD;
                  treating physician and study team as applicable.&#xD;
&#xD;
               2. Subjects at study entry with bone marrow malignant replacement estimated at less&#xD;
                  than 80% of total cellularity will need to have stable disease or disease that is&#xD;
                  less than 80% in the marrow as determined and approved by the PI, treating&#xD;
                  physician and study team as applicable.&#xD;
&#xD;
             Note: Bone marrow sampling is not an accurate reflection of disease burden because&#xD;
             only a small biopsy is obtained to represent a patchy disease distributed all over the&#xD;
             marrow. Hence these numbers and in the absence of severe cytopenias that are&#xD;
             attributed to documented marrow replacement with malignant cells should not be&#xD;
             formidable as is and borderline cases should be discussed and approved by the PI and&#xD;
             the study team as applicable before moving forward.&#xD;
&#xD;
          2. Solid Mass Forming CD4+ lymphomas: (in lymph nodes or extra nodal sites)&#xD;
&#xD;
               1. Stage IV disease: Subjects with Stage IV disease that is deemed bulky by the&#xD;
                  standard definition of the presence of at least one site with a mass that is &gt;&#xD;
                  7.5 cm in largest diameter who have a 50% estimated reduction of total disease&#xD;
                  burden by imagining as read by radiology after conditioning chemotherapy are&#xD;
                  eligible to continue on study. In borderline cases, where they don't meet this&#xD;
                  criteria but are thought to have bulky disease by the treating investigator,&#xD;
                  clinical judgment will be required to determine eligibility of subjects who&#xD;
                  experience for example mixed responses; improved sites and progressed sites. In&#xD;
                  these cases, the PI, treating physician, and study team as applicable should&#xD;
                  agree and document that total disease burden has been reduced by about 50% when&#xD;
                  taking all sites involved into account as there is no objective method to make&#xD;
                  this estimated reduction if some areas improve and others don't, or even new&#xD;
                  sites arise.&#xD;
&#xD;
               2. Stage I-III disease: Subjects with stage I-III ( No extra nodal disease) who&#xD;
                  continue to have stable disease or better after conditioning chemotherapy are&#xD;
                  eligible to continue on study.&#xD;
&#xD;
          3. Skin Disease a. There will be no response or non-response criteria assessed that will&#xD;
             be specific to skin disease since disease burden is almost never expected to be high&#xD;
             without skin barrier violation and often involve infections that would make subjects&#xD;
             ineligible at the time&#xD;
&#xD;
        Eligibility for CD4CAR infusion:&#xD;
&#xD;
        Inclusion&#xD;
&#xD;
          1. Afebrile and not receiving antipyretics, and no evidence of active infection&#xD;
&#xD;
          2. Specific organ function criteria for cardiac, renal, and liver function must be&#xD;
             similar to initial inclusion values. Tests such as echocardiogram and PFTs need not be&#xD;
             repeated if within 6 weeks of initial assessment.&#xD;
&#xD;
          3. Negative pregnancy testing (if applicable)&#xD;
&#xD;
          4. If previous history of corticosteroid chemotherapy, subject must be off all but&#xD;
             adrenal replacement doses 3 days before the CD4CAR infusion.&#xD;
&#xD;
          5. Planned infusion dose was successfully manufactured and met release criteria.&#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>Huda Salman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Indiana University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Tiffanie Skillman, RN</last_name>
    <phone>317-278-5620</phone>
    <email>tskillma@iu.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Huda Salman, MD</last_name>
    <phone>(317) 278-9504</phone>
    <email>hsalman@iu.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Indiana University Melvin and Bren Simon Comprehensive Cancer Center</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Huda Salman, MD</last_name>
      <phone>317-278-9504</phone>
      <email>hsalman@iu.edu</email>
    </contact>
    <investigator>
      <last_name>Huda Salman, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Stony Brook Cancer Center</name>
      <address>
        <city>Stony Brook</city>
        <state>New York</state>
        <zip>11794</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>December 19, 2018</study_first_submitted>
  <study_first_submitted_qc>February 1, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>September 15, 2023</last_update_submitted>
  <last_update_submitted_qc>September 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Indiana University</investigator_affiliation>
    <investigator_full_name>Huda Salman</investigator_full_name>
    <investigator_title>Director, Hematologic Malignancies Service and Director, CAR T Cellular Therapy Program</investigator_title>
  </responsible_party>
  <keyword>CD4; T-cell; lymphoma; leukemia; chimeric antigen; CAR-T</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, T-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>


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/NCT03829540
org study id: CTO-IUSCCC-ICG122-101
secondary id: FD-R-006820-01
nct id: NCT03829540
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study is designed as a single arm open label Phase I, 3x3, multicenter study of
      CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in patients with relapsed
      or refractory T-cell leukemia and lymphoma. Specifically, the study will evaluate the safety
      and feasibility of CD4CAR T-cells. Funding Source - FDA OOPD
The study will be performed as a dose-escalation protocol. Due to the relatively low
      incidence and prevalence of cluster of differentiation 4-positive (CD4+) hematological
      malignancies and the associated aggressive nature of these diseases and the sequel of
      treatment failure, the investigators expect to recruit 20 subjects at Stony Brook, Indiana
      University, and other identified sites with an expected dropout rate of 25% primarily due to
      rapid progression or death and screen and or manufacturing failure. Taking this into account,
      the investigators expect to treat 15 patients. The study will utilize autologous CD4CAR
      T-cells that are engineered to express a chimeric antigen receptor (CAR) targeting CD4 that
      is linked to the cluster of differentiation 28 (CD28), 4-1BB, cluster of differentiation
      3-zeta (CD3ζ) signaling chains (third generation CAR).

      At entry, disease status will be staged and investigators will determine if the subject has
      adequate T cell number for apheresis and for manufacturing CD4CAR cells. Qualifying subjects
      will be leukapheresed to obtain large numbers of peripheral blood mononuclear cells (PBMC)
      for the manufacturing. Next, participants will receive conditioning chemotherapy. If tumor
      burden is sufficiently reduced (screening step), participants will receive CD4CAR cells by
      infusion on Day 0 of treatment.

      For cell harvest, 12-15-liter apheresis procedure will be performed at the apheresis center
      with the intention to harvest at least 50x10^9-nucleated cells to manufacture CD4CAR T-cells.
      A portion of the pheresed cells will also be cryopreserved for FDA look-back requirements and
      for further research. The T-cells will be purified from the PBMC, transduced with CD4CAR
      lentiviral vector, expanded in vitro, and then frozen for administration. Each dose will be
      stored in either one or two bags. The route of administration is by IV infusion and the
      duration of infusion will be approximately 20 minutes. Each bag will contain an aliquot
      (30-50 mL) of liquid suitable for freezing, and containing the following infusible grade
      reagents (% v/v): 62.5cc Plasmalyte-A 5% dextrose; 7.5cc Pure dimethylsulfoxide (DMSO), 20cc
      of 25% Human Serum Albumin, and 10cc Dextran 40. The cell product is expected to be ready for
      release approximately 3-4 weeks after apheresis.

      If the disease progresses during the manufacturing period participants may be excluded from
      the study. Minimal chemotherapy to keep the disease under control in the meanwhile is allowed
      if deemed necessary by investigators.

      A single dose of CD4CAR transduced T cells will consist of the cell number for the dose level
      to be infused.

      Post-infusion monitoring of CD4CAR T-cells: Subjects will have blood drawn for cytokine
      levels, CD4CAR Transgene Copy Number (PCR) and flow cytometry in order to evaluate the
      presence of CD4CAR cells on days 0, 1, 3, 5, 7, 14, 28, and 42 following infusion (or as
      clinically needed). Cytokines levels will be evaluated per schedule above in addition to and
      as needed every 8 +/- 2 hours as feasible if/when CRS occurs and until resolution. Active
      monitoring of fungal and viral infections during treatment while utilizing standard
      prophylaxis recommended for HIV-positive patients with T-cell aplasia and those undergoing
      allogeneic stem cell transplant. Investigators plan to collect data about clinicoradiologic
      measurements of residual tumor burden starting on day 6 and weekly afterward until day 42 and
      then monthly for 6 months. This will be followed by quarterly clinical evaluations for the
      next two (2) years with a medical history, physical examination, and comprehensive blood
      testing. After these short- and intermediate-term evaluations are performed, these patients
      will enter a rollover study to assess for disease-free survival (DFS), relapse, and the
      development of other health problems or malignancies where follow-up will be up tp twice a
      year by phone and a questionnaire for an additional thirteen (13) years. The treating
      physician will decide to proceed with allogeneic or autologous transplant when needed.

      Dose of CD4CAR description: the main objective of this study is to establish a recommended
      dose and/or schedule of CD4CAR. The guiding principle for dose escalation in phase I is to
      avoid unnecessary exposure of patients to sub-therapeutic doses (i.e., to treat as many
      patients as possible within the therapeutic dose range) while preserving safety and
      maintaining rapid accrual. Investigators will use the rule-based traditional Phase I "3+3"
      design for the evaluation of safety. Based on lab experience in mice the starting dose (dose
      level 1) for the first cohort of three patients in phase I portion of the study will be
      8x10^5 cells. The dose escalation or de-escalation will follow a modified Fibonacci sequence
      as below.

      If more than one patient out of the first cohort of three patients in dose level 1 experience
      dose limiting toxicity (DLT), the trial will be placed on hold. If zero or one out of three
      patients in the first cohort of dose level 1 experience DLT, three more patients will be
      enrolled at dose level 1; the dose escalation continues until at least two patients among a
      cohort of six patients experience DLT (i.e., ≥33% of patients with a DLT at this dose level)

        -  If one of the first three patients in dose level 1 experiences a DLT, three more
           patients will be treated at dose level 1.

        -  If none of the three patients or only one of the 6 patients in the dose level 1
           experiences a DLT, the dose escalation continues to the dose level 2

        -  If one of the first three patients in dose level 2 experience a DLT, three more patients
           will be treated at dose level 2

        -  If none of the three patients or only one of the 6 patients in the dose level2
           experiences a DLT, the dose escalation continues to the dose level 3

        -  If one of the first three patients in dose level 3 experiences a DLT, three more
           patients will be treated at dose level 3

        -  If none of the three patients or only one of the 6 patients in the dose level 3
           experiences a DLT, dose level 3 will be declared the maximum tolerated dose (MTD) and
           will be used as the recommended phase II dose (RP2D) for the phase II portion of the
           study.

      In summary, the dose escalation continues until at least two patients among a cohort of six
      patients experience DLT (i.e., ≥33% of patients with a DLT at that dose level). The
      recommended dose for phase II trials is defined as one dose level below this toxic dose
      level. Since some grade 3 and possibly 4 toxicities are highly likely to be reversible, grade
      3 infectious, hematological and vascular toxicities will not be considered DLTs mandating
      dose reduction. Also allergic or infusion-related reactions ≤ grade 3 will not be counted as
      DLTs. There will be no intra-patient dose escalation or reduction.

      To allow for full spectrum toxicity duration evaluation and reporting, no patients within the
      same or a different cohort will be initiated on lymphodepleting chemotherapy sooner than 42
      days from the initiation date of the preceding patient.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
time frame: 18-24 months
description: To assess the safety and feasibility of the chimeric antigen receptor T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells) according to CTCAE grading. The feasibility of treating those adverse events and their duration till resolution will also be described.
measure: Duration of in vivo survival of the CD4CAR.
time frame: 18-24 months
description: Persistence of CD4CAR will be monitored by measuring the CD4CAR transgene copy number at variable time points.
measure: Rate of manufacturing failure
time frame: 18-24 months
description: The number of failed manufacturing attempts of CD4 CAR, per subject and overall, in this patient population. Manufacturing failure is defined as failure to manufacture the adequate CD4CAR cell dose for the particular cohort the patient is enrolled on. Three manufacturing attempts per patient are allowed.
measure: Clinical Response
time frame: 18-24 months
description: Clinical response to T-cell infusion will be evaluated by comparing disease before and after infusion identified by:
standard imaging (PET CT or PET MRI) for lymphoma patients
bone marrow biopsy for leukemia patients
peripheral blood cells morphology, flow cytometry panel, immunohistochemistry, and other blood molecular markers for both lymphoma and leukemia.
measure: Trafficking of CD4CAR at tumor sites and at sites with significant toxicity
time frame: 18-24 months
description: Quantification of both of CD4CAR by flowcytometry and transgene copy number by polymerase chain reaction (PCR) will be measured at tumor sites in bone marrow and lymph nodes at variable time points if applicable. Same tests will be done on biopsies of organs that shows significant toxicity if need be.
measure: Number of participants with immune reactions against CD4CAR
time frame: 18-24 months
description: The absolute and relative number of subjects who develop immune reactions against the treatment over a period of 2 years. Human anti-mouse antibody (HAMA) ELISA tests will be carried out in the blood of participants at multiple times after initial treatment.
measure: Serum cytokines levels
time frame: 18-24 months
description: Serum cytokine levels will be evaluated on Day 2, 4, 7, 11, 14, 21, 28 in addition to planned monitoring during CRS every 8 hours and until resolution. These cytokines include interleukin-6 (IL-6), interferon-γ, tumor necrosis factor, IL-2, IL-2-receptor-a, IL-8, and IL-10
measure: Determine CD4CAR cell subsets during proliferation
time frame: 18-24 months
description: Participants' blood will be tested by flow cytometry to determine the relative abundance of cellular subsets that may result from CD4CAR T cells upon their proliferation. These subsets include Tcm, Tem, and Tregs.
arm group label: Treatment
arm group type: Experimental
description: Redirected autologous T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells)
intervention type: Biological
intervention name: CD4CAR
description: CD4CAR cells transduced with a lentiviral vector to express the single-chain variable fragment (scFv) nucleotide sequence of the anti-CD4 molecule derived from humanized monoclonal ibalizumab and the intracellular domains of CD28 and 4-1BB co-activators fused to the CD3ζ T-cell activation signaling domain administered by IV infusions as a single dose
arm group label: Treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Huda Salman, MD
role: Principal Investigator
affiliation: Indiana University
last name: Tiffanie Skillman, RN
phone: 317-278-5620
email: tskillma@iu.edu
last name: Huda Salman, MD
phone: (317) 278-9504
email: hsalman@iu.edu
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Indiana University
investigator full name: Huda Salman
investigator title: Director, Hematologic Malignancies Service and Director, CAR T Cellular Therapy Program
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Leukemia, T-Cell
sharing ipd: No