<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/NCT03016377</url>
  </required_header>
  <id_info>
    <org_study_id>LCCC1541-ATL</org_study_id>
    <nct_id>NCT03016377</nct_id>
  </id_info>
  <brief_title>Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL</brief_title>
  <official_title>Administration of Autologous CAR-T Cells Targeting the CD19 Antigen and Containing the Inducible caspase9 Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UNC Lineberger Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bellicum Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>UNC Lineberger Comprehensive Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The body has different ways of fighting infection and disease. No single way is effective at&#xD;
      fighting cancer. This research study combines two different ways of fighting disease:&#xD;
      antibodies and T cells. Antibodies are proteins that protect the body from disease caused by&#xD;
      bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which&#xD;
      stops them from growing and causing bad effects. T cells, also called T lymphocytes, are&#xD;
      special infection-fighting blood cells that can kill other cells, including tumor cells or&#xD;
      cells that are infected. Both antibodies and T cells have been used to treat patients with&#xD;
      cancers. They both have shown promise, but neither alone has been sufficient to cure most&#xD;
      patients. This study combines both T cells and antibodies to try to create a more effective&#xD;
      treatment. This investigational treatment is called autologous T lymphocyte chimeric antigen&#xD;
      receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration.&#xD;
&#xD;
      In previous studies, it has been shown that a new gene can be put into T cells that will&#xD;
      increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes&#xD;
      make up the chemical structure carrying the genetic information that may determine human&#xD;
      characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells&#xD;
      makes a piece of an antibody called anti-CD19. This antibody can flow through the blood and&#xD;
      can find and stick to leukemia cells because these leukemia cells have a substance on their&#xD;
      surface called CD19. Anti-CD19 antibodies have been used to treat people with leukemia but&#xD;
      have not been strong enough to cure most patients. For this study, the anti-CD19 antibody has&#xD;
      been changed so that instead of floating free in the blood a piece of it is now joined to the&#xD;
      surface of the T cells. Only the part of the antibody that sticks to the leukemia cells is&#xD;
      attached to the T cells instead of the entire antibody. When an antibody is joined to a T&#xD;
      cell in this way it is called a chimeric receptor. These CD19 chimeric (combination)&#xD;
      receptor-activated T cells kill some of the tumor, but they do not last very long in the body&#xD;
      and so their chances of fighting the cancer are unknown.&#xD;
&#xD;
      Preliminary results of giving ATLCAR.CD19 cells to leukemia patients have been encouraging;&#xD;
      however, many subjects receiving this treatment have experienced unwanted side effects&#xD;
      including neurotoxicity and/or cytokine release syndrome (also referred to as cytokine storm&#xD;
      or an infusion reaction). Cytokines are small proteins that interreact as e signals to other&#xD;
      cells and are the way cells talk to one another. During cytokine release syndrome, too many&#xD;
      cytokines are released and too many cells in your body react to their release. Symptoms&#xD;
      resulting from cytokine release syndrome vary from flu-like symptoms to more severe side&#xD;
      effects such as cardiac arrest, multi-system organ failure or death. We predict that about&#xD;
      50% of patients on this study will experience mild to severe cytokine release syndrome.&#xD;
&#xD;
      To help reduce cytokine release syndrome symptoms in future patients, a safety switch has&#xD;
      been added to the ATLCAR.CD19 cells that can cause the cells to become dormant or &quot;go to&#xD;
      sleep&quot;. The safety switch is called inducible caspase 9 or iC9. The modified ATLCAR.CD19&#xD;
      cells with the safety switch are referred to as iC9-CAR19 cells.&#xD;
&#xD;
      The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and&#xD;
      tolerable (there are not too many unwanted effects). Researchers has previously tested&#xD;
      different doses of the iC9-CAR19. An effective dose that had the least number of unwanted&#xD;
      side effects in patients was identified. It was planned to test this dose in more patients to&#xD;
      learn more about its effect in the body. This type of research study is called a dose&#xD;
      expansion study. It will allow the investigators to collect more information about the effect&#xD;
      of this dose in treating of certain type of cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      LCCC1541-ATL is a Phase I/Phase II dose finding trial to determine if chimeric antigen&#xD;
      receptor T (CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9&#xD;
      safety switch can be safely administered to adult and pediatric subjects with relapsed or&#xD;
      refractory CD19+ acute lymphoblastic leukemia (ALL).&#xD;
&#xD;
      OUTLINE&#xD;
&#xD;
      Cell Procurement&#xD;
&#xD;
      Peripheral blood, up to 300 mL total (in up to 3 collections) will be obtained from subjects&#xD;
      for cell procurement. In subjects with inadequate lymphocyte count in the peripheral blood, a&#xD;
      leukopheresis may be performed to isolate sufficient T cells. The parameters for apheresis&#xD;
      will be up to 2 blood volumes.&#xD;
&#xD;
      Lymphodepleting Regimen&#xD;
&#xD;
      Subjects will receive a lymphodepleting regimen of fludarabine 25 mg/m2/day administered IV&#xD;
      over 30 min for three consecutive days and a single IV dose of cyclophosphamide 900 mg/m2&#xD;
      administered over 1 hour on the fourth day. If iC9-CAR19 T cell infusion is delayed for &gt;4&#xD;
      weeks, lymphodepletion may be repeated prior to iC9-CAR19 T cell infusion.&#xD;
&#xD;
      Administration of iC9-CAR19 T Cells&#xD;
&#xD;
      Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will&#xD;
      receive iC9-CAR19 T cells within 2-14 days after completing the pre-conditioning chemotherapy&#xD;
      regimen. We will administer iC9-CAR19 post lymphodepletion at dose levels specified. A phase&#xD;
      I trial performed by Lee et al established that 1×106 CAR19+ T cells/kg was safe and&#xD;
      associated with significant in vivo expansion and we anticipate similar results with&#xD;
      iC9-CAR19+ T cells.&#xD;
&#xD;
      Second Cell Infusion Requirements:&#xD;
&#xD;
      Subjects will be offered a second infusion based on B-cell recovery and MRD status &gt;4 weeks&#xD;
      after the initial infusion if cells are available or if the subject has sufficient stored&#xD;
      peripheral blood to manufacture additional iC9-CAR19 T cells.&#xD;
&#xD;
      Duration of Therapy&#xD;
&#xD;
      Therapy in LCCC1541-ATL involves 1 infusion of iC9-CAR19 cells. Treatment with one infusion&#xD;
      will be administered unless:&#xD;
&#xD;
        -  Subject decides to withdraw from study treatment, or&#xD;
&#xD;
        -  General or specific changes in the subject's condition render the subject unacceptable&#xD;
           for further treatment in the judgment of the investigator.&#xD;
&#xD;
      A second infusion with prior lymphodepletion will be given to subjects enrolled in the&#xD;
      expansion cohort and to subjects enrolled in the dose escalation cohort once the RP2D is&#xD;
      reached if they meet the eligibility requirements for lymphodepletion and infusion.&#xD;
      Specifically, only subjects with the following characteristics will be offered a second&#xD;
      infusion:&#xD;
&#xD;
        -  B-cell recovery (defined as absolute CD19+ cell count &gt;50/μL in the blood or bone marrow&#xD;
           within 6 months of initial infusion AND/OR&#xD;
&#xD;
        -  MRD positive (defined as ≥0.01% as assessed by multi-parameter flow cytometry) with&#xD;
           CD19+ expression at any time after the initial infusion.&#xD;
&#xD;
        -  *Note that subjects who receive dose level 1 in the dose escalation will receive the&#xD;
           RP2D for their second infusion, if applicable.&#xD;
&#xD;
      Duration of Follow-up&#xD;
&#xD;
      Subjects will be followed for up to 15 years after the final iC9-CAR19 T-cell infusion for&#xD;
      RCR evaluation or until death, whichever occurs first. Subjects removed from study for&#xD;
      unacceptable adverse events will be followed until resolution or stabilization of the adverse&#xD;
      event.&#xD;
&#xD;
      Subjects who receive new therapy (such as hematopoietic stem cell transplant) after a cell&#xD;
      product administration will still be required to complete abbreviated follow up procedures.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 22, 2012</start_date>
  <completion_date type="Anticipated">April 22, 2041</completion_date>
  <primary_completion_date type="Anticipated">April 22, 2026</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells</measure>
    <time_frame>4 weeks</time_frame>
    <description>Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of dose limiting toxicity to identify recommended phase 2 dose (RP2D)</measure>
    <time_frame>4 weeks</time_frame>
    <description>The recommended phase 2 dose of iC9-CAR19 cells in adult and pediatric subjects will be determined maximum dose at which no more than one out of six patients experiences a dose limiting toxicity (DLT). A DLT is defined according to protocol criteria using the NCI CTCAE, ICANS, and CRS criteria. In general, a DLT is any grade 3 or higher event that is at least possibly related to iC9-CAR19 T cells.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in persistence of iC9-CAR19 T cells in vivo</measure>
    <time_frame>15 years</time_frame>
    <description>Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>15 years</time_frame>
    <description>ORR (Complete Response/Complete Response with incomplete recovery of counts) to first iC9-CAR19 T cell therapy will be determined using National Comprehensive Cancer Network Response Criteria (NCCN) for acute lymphoblastic leukemia. Assessment of minimal residual disease will be included as criterion of response (ie, the percentage of subjects who achieve CRm [defined as minimal residual disease negative complete response] by either flow cytometry or PCR analysis will be determined)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival after infusion of iC9-CAR19 T cells</measure>
    <time_frame>15 years</time_frame>
    <description>Overall survival will be measured from the date of administration of first iC9-CAR19 T cells to the date of death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-free survival rate</measure>
    <time_frame>15 years</time_frame>
    <description>Event free survival rate applies to all subjects and will be measured from the date of administration of first iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from complete response or complete response with incomplete recovery of counts, or death from any cause; subjects not known to have any of these events are censored on the date they were last examined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse-free survival rate</measure>
    <time_frame>15 years</time_frame>
    <description>Relapse-free survival rate will apply only to subjects achieving complete response or complete response with incomplete recovery of counts and measured from the date of achievement of a remission until the date of relapse or death from any cause; subjects not known to have relapsed or died at last follow-up are censored on the date they were last examined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of patient reported symptoms in adult patients using selected symptoms from the NCI PRO-CTCAE</measure>
    <time_frame>15 years</time_frame>
    <description>The NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of 78 symptomatic treatment toxicities.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in patient reported physical functions in adult patients</measure>
    <time_frame>15 years</time_frame>
    <description>Patient reported physical functions in adult patients will be assessed per the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health on a five point Likert scale with higher score indicating better functioning.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in patient reported health-related quality of life in adult patients</measure>
    <time_frame>15 years</time_frame>
    <description>Patient reported health-related quality of life will be assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health health on a five point Likert scale with higher score indicating better functioning.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with adverse events as a measure of safety and tolerability of a second infusion of iC9-CAR19 T cells</measure>
    <time_frame>4 weeks</time_frame>
    <description>Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of measurable residual disease (MRD) clearance in subjects who receive iC9-CAR19 T cells for MRD persistence or MRD-only relapse</measure>
    <time_frame>8 weeks</time_frame>
    <description>Rate of MRD clearance will be defined as the proportion of subjects who enter MRD-negative complete response (CRm) who are treated with one or two infusions of iC9 CAR19 T cells at the time of being in complete response (CR) or Complete Response with incomplete recovery of counts (CRi), but not CRm.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">54</enrollment>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <condition>Immune System Diseases</condition>
  <condition>Immunoproliferative Disorders</condition>
  <arm_group>
    <arm_group_label>iC9-CAR19 cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The 3+3 design in adult subjects and an independent study using 3+3 design in pediatric subjects. The starting dose of 5 x 10^5 transduced cells/kg will enroll 3 adult subjects in the initial cohort. If there are no dose limiting toxicities w/in 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x10^6 transduced cells/kg in adults. If there is toxicity in 1/3 patients in the initial cohort, the cohort will be expanded to enroll up to 6 adult patients. If the dose level 1 is determined to be above the tolerated cell dose, de-escalation would occur to dose level -1 where subjects would receive 1 x 10^5 transduced cells/kg. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before administration of iC9-CAR19 T cells.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Expansion Cohort Second Administration of iC9-CAR19 cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After the recommended phase 2 dose (RP2D) of iC9-CAR19 T cells has been determined in adults, up to 18 additional adult subjects will be enrolled in an expansion cohort at the RP2D. In the expansion cohort, subjects will be offered a second infusion of iC9-CAR19 T cells based on B-cell recovery and minimal residual disease (MRD) status. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before second administration of iC9-CAR19 T cells.&#xD;
Subjects in the expansion cohort who experience ≥grade 2 CRS or ICANS, did not respond to the initial dose of the standard of care treatment will be enrolled in a sub-study of rimiducid.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>iC9-CAR19 cells</intervention_name>
    <description>Three dose levels are being evaluated: dose level -1 (1 x 10^5), dose level 1 (5 x 10^5), and dose level 2 ( 1x 10^6)</description>
    <arm_group_label>Expansion Cohort Second Administration of iC9-CAR19 cells</arm_group_label>
    <arm_group_label>iC9-CAR19 cells</arm_group_label>
    <other_name>CAR.CD19 T cells</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rimiducid</intervention_name>
    <description>Subjects with CRS and ICAN will assign one of two dose levels (DL)s of rimiducid with the standard treatment: 0.05 mg/kg or 0.1 mg/kg for subjects with CRS and 0.01mg/kg or 0.1mg/kg for subjects with ICAN. Subjects will first be enrolled on DL 1 and then enrolled on DL 2, and 0.4mg/kg rimiducid will be given to subjects who did not respond to the initial dose.</description>
    <arm_group_label>Expansion Cohort Second Administration of iC9-CAR19 cells</arm_group_label>
    <arm_group_label>iC9-CAR19 cells</arm_group_label>
    <other_name>AP1903</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>900 mg/m^2 IV over 1 hour on day 4 of lymphodepleting chemotherapy.</description>
    <arm_group_label>Expansion Cohort Second Administration of iC9-CAR19 cells</arm_group_label>
    <arm_group_label>iC9-CAR19 cells</arm_group_label>
    <other_name>Neosar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>25 mg/m^2/day IV over 30 minutes administered for 3 consecutive days.</description>
    <arm_group_label>Expansion Cohort Second Administration of iC9-CAR19 cells</arm_group_label>
    <arm_group_label>iC9-CAR19 cells</arm_group_label>
    <other_name>Fludara</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        All clinical and laboratory data required for determining eligibility must be available in&#xD;
        the subject's medical/research record which will serve as the source document. Subjects may&#xD;
        be transfused with blood products to obtain a hemoglobin level &gt; 7.0 g/dL and platelet&#xD;
        count &gt; 20,000 per μl.&#xD;
&#xD;
        Note: During the period after cell procurement and during iC9-CAR19 T-cell production,&#xD;
        subjects are allowed to receive standard of care intervening therapy for ALL to manage&#xD;
        their disease if the treating physician feels it is in the subject's best interest Common&#xD;
        Inclusion Criteria for all subjects&#xD;
&#xD;
          -  Written informed consent for procurement signed by subject or legal guardian of a&#xD;
             pediatric subject and HIPAA authorization&#xD;
&#xD;
          -  Age 3 to 17 years of age for pediatric subjects (weight must be ≥10 kg), ≥ 18 to 70&#xD;
             years of age for adults at the time of consent.&#xD;
&#xD;
          -  Karnofsky score &gt; 60%, if ≥16 years old, or Lansky performance score of greater than&#xD;
             60% if &lt;16 years old .&#xD;
&#xD;
        Demonstrate adequate renal and hepatic function as defined below; all screening labs to be&#xD;
        obtained within 72 hours prior:&#xD;
&#xD;
        System Laboratory Value Renal* Serum Creatinine (sCr) ≤ 1.5 × ULN) Hepatic: Total bilirubin&#xD;
        (tBili) ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome Aspartate aminotransferase&#xD;
        (AST) ≤ 3.0 × ULN Alanine aminotransferase (ALT) ≤ 3.0 × ULN&#xD;
&#xD;
          -  Females of childbearing potential must have a negative serum pregnancy test within 72&#xD;
             hours prior to procurement. Note: Females are considered of childbearing potential&#xD;
             unless they are premenarchal, surgically sterile (have undergone a hysterectomy,&#xD;
             bilateral tubal ligation, or bilateral oophorectomy) or they are naturally&#xD;
             postmenopausal for at least 12 consecutive months.&#xD;
&#xD;
          -  Females and males of childbearing potential must be willing to abstain from&#xD;
             heterosexual activity or to use two forms of effective methods of contraception from&#xD;
             the time of informed consent until 3 months after treatment discontinuation. The two&#xD;
             contraception methods can be comprised of two barrier methods, or a barrier method&#xD;
             plus a hormonal method. Female participants will inform their male partners that they&#xD;
             must use the methods of birth control required by the protocol.&#xD;
&#xD;
          -  Male subjects with female partners must have had a prior vasectomy or agree to use an&#xD;
             adequate method of contraception (i.e., double barrier method: condom plus spermicidal&#xD;
             agent) starting with the first dose of study therapy through 3 months after the last&#xD;
             dose of study therapy. As determined by the enrolling physician or protocol designee,&#xD;
             ability of the subject to understand and comply with study procedures.&#xD;
&#xD;
        Inclusion Criteria for Cell Procurement&#xD;
&#xD;
          -  Relapsed or refractory precursor B cell ALL:&#xD;
&#xD;
               -  2nd or greater bone marrow or central nervous system (CNS) relapse,&#xD;
&#xD;
               -  Any bone marrow or CNS relapse &gt;100 days after allogeneic stem cell transplant,&#xD;
                  Primary refractory ALL defined as no complete response after 2 cycles of a&#xD;
                  standard of care chemotherapy regimen, or&#xD;
&#xD;
               -  For adult subjects: first bone marrow or CNS relapse with duration of first CR &lt;1&#xD;
                  year, or CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for treatment&#xD;
                  of relapse&#xD;
&#xD;
               -  Subjects with isolated non-CNS extramedullary disease will be eligible as long as&#xD;
                  the time-of-remission criteria above for bone marrow and CNS relapses or primary&#xD;
                  refractory ALL are met and the biopsy for extramedullary disease confirms CD19&#xD;
                  expression&#xD;
&#xD;
               -  For pediatric subjects: first bone marrow, CNS or isolated non-CNS extramedullary&#xD;
                  relapse refractory to more than 1 cycle of standard therapy for relapsed ALL&#xD;
&#xD;
               -  While active CNS3 leukemia will be excluded, subjects with concurrent CNS3&#xD;
                  disease and bone marrow relapse who have responded to CNS-directed therapy prior&#xD;
                  to enrollment will be allowed to participate. Intrathecal chemotherapy will be&#xD;
                  allowed to continue between lymphodepleting chemotherapy and cell infusion.&#xD;
&#xD;
               -  Subjects with CNS2 disease and concurrent bone marrow relapse will be eligible.&#xD;
                  Intrathecal chemotherapy will be allowed to continue between lymphodepleting&#xD;
                  chemotherapy and cell infusion&#xD;
&#xD;
               -  Subjects who have previously achieved remission with no detectible measurable&#xD;
                  residual disease (MRD) by multi-parameter flow cytometry, and who have re-&#xD;
                  developed CD19+ MRD measured by multi-parameter flow cytometry will be eligible,&#xD;
                  provided that the duration of first MRD-negative CR was &lt;1 year, MRD- negative&#xD;
                  CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for treatment of MRD&#xD;
                  recurrence, or MRD reappearance occurs during second or subsequent CR.&#xD;
&#xD;
               -  Subjects who have persistent CD19+ MRD measured by multi-parameter flow cytometry&#xD;
                  after 3 cycles of initial chemotherapy, and have persistence of CD19+ MRD after&#xD;
                  one or more cycles of blinatumomab.&#xD;
&#xD;
          -  Subjects with Ph+ ALL will be eligible if they have failed ≥ 2 ABL tyrosine kinase&#xD;
             inhibitors, relapsed after allogeneic stem cell transplant or have CD19+ MRD. Subjects&#xD;
             with the T315I ABL kinase point mutation will be eligible if they have failed&#xD;
             ponatinib-containing therapy, regardless of the number of prior ABL tyrosine kinase&#xD;
             inhibitors.&#xD;
&#xD;
          -  CD19 positivity of lymphoblasts confirmed by flow cytometry or IHC per institutional&#xD;
             standards.&#xD;
&#xD;
          -  Life expectancy ≥ 12 weeks.&#xD;
&#xD;
          -  Demonstrate adequate renal and hepatic function as defined below; all screening labs&#xD;
             to be obtained within 72 hours prior to procurement.&#xD;
&#xD;
             *For pediatric patients, adequate renal function is defined as below: Age Maximum&#xD;
             Serum Creatinine (mg/dL) Both (Male, Female) 3 to &lt;6 years ≤0.8 6 to &lt;10 years ≤1 10&#xD;
             to &lt;13 years ≤1.2 13 to &lt;16 years (Male) ≤1.5 / Female ≤1.4 16 to &lt;18 years (Male)&#xD;
             ≤1.7 / Female ≤1.4&#xD;
&#xD;
          -  Subjects currently receiving &quot;maintenance&quot; doses of chemotherapy are eligible and the&#xD;
             need for intrathecal prophylaxis prior to procurement is left to the discretion of the&#xD;
             investigator. Maintenance doses of systemic chemotherapy are defined as methotrexate&#xD;
             ≤30 mg/m2/week, mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days.&#xD;
             Maintenance therapy in patients with Ph+ leukemia may also contain tyrosine kinase&#xD;
             inhibitors (TKIs) targeting BCR-ABL, at the discretion of the investigator.&#xD;
             Corticosteroid- containing maintenance therapy is permitted only if corticosteroids&#xD;
             are administered &gt;14 days prior to procurement.&#xD;
&#xD;
        Exclusion Criteria for Cell Procurement&#xD;
&#xD;
        Subjects meeting any of the following criteria cannot be enrolled in this study:&#xD;
&#xD;
          -  Subjects with relapsed fulminant CD19+ ALL that is rapidly progressing with&#xD;
             circulating lymphoblasts that are rising in proportion to &gt;50% of circulating white&#xD;
             blood cells.&#xD;
&#xD;
          -  Intrathecal chemotherapy will be allowed to continue between cell procurement and&#xD;
             lymphodepleting chemotherapy.&#xD;
&#xD;
          -  Pregnant or breastfeeding (Note: breast milk cannot be stored for future use if the&#xD;
             milk is collected while the mother is being treated on study).&#xD;
&#xD;
          -  Has a known additional malignancy that is active and/or progressive requiring&#xD;
             treatment; exceptions include basal cell or squamous cell skin cancer, in situ&#xD;
             cervical or bladder cancer, or other cancer for which the subject has been&#xD;
             disease-free for at least five years.&#xD;
&#xD;
          -  Subjects must not have tumor in a location where enlargement could cause airway&#xD;
             obstruction.&#xD;
&#xD;
          -  Subjects may not have an oxygen requirement as defined by pulse oximetry of &lt;90% on&#xD;
             room air.&#xD;
&#xD;
          -  Subjects must not have left ventricular ejection fraction of &lt;40% (shortening fraction&#xD;
             &lt;27% for pediatric subjects) as measured by echocardiogram or MUGA.&#xD;
&#xD;
          -  Patients with the following systemic viral infections will be excluded: active HIV,&#xD;
             HTLV, HBV, HCV (tests can be pending at the time of cell procurement; only those&#xD;
             samples confirming lack of active infection will be used to generate transduced&#xD;
             cells). Note: To meet eligibility subjects are required to not be positive for HIV&#xD;
             antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for&#xD;
             HTLV1 and 2, negative for Hepatitis B surface antigen, or negative for HCV antibody or&#xD;
             HCV viral load.&#xD;
&#xD;
          -  Patients who are on treatment for other active uncontrolled infections (not referenced&#xD;
             above) with resolution of signs/symptoms are not excluded. Non-influenza, non-RSV,&#xD;
             isolated upper respiratory infections are not excluded. Other active uncontrolled&#xD;
             infections will be excluded.&#xD;
&#xD;
          -  Prior to procurement current use of systemic corticosteroids at doses ≥10 mg/day&#xD;
             prednisone or its equivalent; those receiving &lt;10 mg/day may be enrolled at discretion&#xD;
             of investigator. (Note: Corticosteroid use with doses at the discretion of the&#xD;
             treating physician are allowed after procurement up to the beginning of&#xD;
             lymphodepletion. Corticosteroid use is contraindicated following iC9-CAR19 infusion&#xD;
             unless medically necessary e.g., to treat CRS).&#xD;
&#xD;
          -  Physiologic replacement with hydrocortisone is allowed at doses 6-12 mg/m2/day, or&#xD;
             equivalent.&#xD;
&#xD;
          -  Received anti-CD19 antibody-based therapy or cytotoxic chemotherapy not described as&#xD;
             maintenance therapy (within 2 weeks of procurement per section).&#xD;
&#xD;
        Inclusion Criteria for Lymphodepletion:&#xD;
&#xD;
          -  Relapsed or refractory precursor B cell ALL, confirmed by presence of blasts in the&#xD;
             blood or bone marrow (≥5%) or in any extramedullary site. Subjects who have previously&#xD;
             achieved remission with no detectible measurable residual disease (MRD) by multi-&#xD;
             parameter flow cytometry, and who have re-developed CD19+ MRD measured by multi-&#xD;
             parameter flow cytometry are eligible, provided that the duration of first&#xD;
             MRD-negative CR was &lt;1 year, MRD-negative CR1 duration ≥1 year and refractory to ≥1&#xD;
             cycle of therapy for treatment of MRD recurrence/relapse, or MRD-recurrence in second&#xD;
             or subsequent morphologic CR. Additionally, subjects who have persistent CD19+ MRD&#xD;
             measured by multi-parameter flow cytometry after 3 cycles of initial chemotherapy, and&#xD;
             have persistence of CD19+ MRD after one or more cycles of blinatumomab are eligible to&#xD;
             participate. Because CNS leukemia is not curable with conventional therapies, subjects&#xD;
             who met inclusion criterion for CNS leukemia at the time of procurement will be&#xD;
             eligible for lymphodepletion even if intrathecal or systemic chemotherapy has rendered&#xD;
             their cerebrospinal fluid free of lymphoblasts prior to lymphodepletion.&#xD;
&#xD;
          -  Life expectancy ≥ 12 weeks.&#xD;
&#xD;
          -  Subjects who have received prior therapy with murine antibodies must have&#xD;
             documentation of absence of human anti-mouse antibodies (HAMA) prior to&#xD;
             lymphodepletion on this study.&#xD;
&#xD;
        Demonstrate adequate renal and hepatic function as defined below; all screening labs to be&#xD;
        obtained within 72 hours prior to lymphodepletion.&#xD;
&#xD;
          -  For pediatric patients, adequate renal function is defined as below:&#xD;
&#xD;
        Age Maximum Serum Creatinine (mg/dL) Both Male/Female 3 to &lt;6 years ≤0.8 6 to &lt;10 years ≤1&#xD;
        10 to &lt;13 years ≤1.2 13 to &lt;16 years (Male) ≤1.5/ (Female) ≤1.4 16 to &lt;18 years (Male)&#xD;
        ≤1.7/(Female) ≤1.4&#xD;
&#xD;
          -  As determined by the enrolling physician or protocol designee, ability of the subject&#xD;
             to understand and comply with study procedures.&#xD;
&#xD;
          -  For subjects who receive chemotherapy between cell procurement and lymphodepletion,&#xD;
             washout periods as described in exclusion criteria sections 4.4.5 to 4.4.11 between&#xD;
             chemotherapy and the beginning of lymphodepletion will be required.&#xD;
&#xD;
          -  Subjects must have autologous transduced activated T cells that meet the Certificate&#xD;
             of Analysis (CofA) acceptance criteria.&#xD;
&#xD;
        Exclusion Criteria for Lymphodepletion&#xD;
&#xD;
        Subjects meeting any of the following criteria cannot be enrolled in this study:&#xD;
&#xD;
          -  Pregnant or breastfeeding (Note: breast milk cannot be stored for future use if the&#xD;
             milk is collected while the mother is being treated on study).&#xD;
&#xD;
          -  Has a known additional malignancy that is active and/or progressive requiring&#xD;
             treatment; exceptions include basal cell or squamous cell skin cancer, in situ&#xD;
             cervical or bladder cancer, or other cancer for which the subject has been&#xD;
             disease-free for at least five years.&#xD;
&#xD;
          -  Subjects must not have tumor in a location where enlargement could cause airway&#xD;
             obstruction.&#xD;
&#xD;
          -  Subjects may not have an oxygen requirement as defined by pulse oximetry of &lt;90% on&#xD;
             room air.&#xD;
&#xD;
          -  Treatment with any investigational drug within 14 days (i.e., two weeks) prior to&#xD;
             lymphodepletion or has received any tumor vaccines within the previous five weeks&#xD;
             prior to lymphodepletion.&#xD;
&#xD;
          -  Subject has received pegylated-asparaginase ≤3 weeks prior to lymphodepletion.&#xD;
&#xD;
          -  Radiotherapy to a non-CNS site completed &lt;1 week prior to lymphodepletion, or CNS&#xD;
             directed radiation completed &lt;7 weeks prior to lymphodepletion.&#xD;
&#xD;
          -  Subject is receiving following drugs &lt;1 week prior to lymphodepletion: salvage&#xD;
             chemotherapy (e.g. clofarabine, cytosine arabinoside &gt; 100 mg/m2, anthracyclines,&#xD;
             cyclophosphamide, methotrexate ≥ 25 mg/m2)..&#xD;
&#xD;
          -  Any systemic drug used for GVHD must be stopped &gt;3 weeks prior to lymphodepletion&#xD;
             (e.g. calcineurin inhibitors, methotrexate or other chemotherapy drugs,&#xD;
             mycophenolyate, rapamycin, thalidomide, or immunosuppressive antibodies such as&#xD;
             anti-CD20 (rituximab), anti-TNF, anti-IL6 or anti-IL6R, systemic steroids).&#xD;
&#xD;
          -  The following drugs must be stopped prior to the beginning of lymphodepleting&#xD;
             chemotherapy: tyrosine kinase inhibitors, hydroxyurea, vincristine, 6-mercaptopurine,&#xD;
             6- thioguanine, methotrexate &lt;25 mg/m2, cytosine arabinoside &lt;100 mg/m2/day, and&#xD;
             asparaginase (non-pegylated). These drugs should not be administered concomitantly or&#xD;
             following lymphodepleting chemotherapy .&#xD;
&#xD;
          -  CNS prophylaxis or treatment of CNS leukemia with intrathecal methotrexate, cytarabine&#xD;
             and/or hydrocortisone treatment must be stopped prior to lymphodepleting chemotherapy.&#xD;
&#xD;
          -  Patients with the following systemic viral infections will be excluded: active HIV,&#xD;
             HTLV, HBV, HCV. Note: To meet eligibility subjects are required to be negative for HIV&#xD;
             antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for&#xD;
             HTLV1 and 2, negative for Hepatitis B surface antigen, or negative for HCV antibody or&#xD;
             HCV viral load.&#xD;
&#xD;
          -  Patients who are on treatment for other active uncontrolled infections (not referenced&#xD;
             above) with resolution of signs/symptoms are not excluded. Non-influenza, non-RSV,&#xD;
             isolated upper respiratory infections are not excluded. Other active uncontrolled&#xD;
             infections will be excluded.&#xD;
&#xD;
          -  Use of systemic corticosteroids at doses ≥10 mg/day prednisone or its equivalent;&#xD;
             those receiving &lt;10 mg/day may be enrolled at discretion of investigator. (Note:&#xD;
             Corticosteroid use with doses at the discretion of the treating physician are allowed&#xD;
             after procurement up to the beginning of lymphodepletion.).&#xD;
&#xD;
        Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent.&#xD;
&#xD;
        Inclusion Criteria- iC9-CAR19 Cell Infusion&#xD;
&#xD;
          -  Subjects must fulfill all of the following inclusion criteria to participate in this&#xD;
             study:&#xD;
&#xD;
          -  As determined by the enrolling physician or protocol designee, ability of the subject&#xD;
             to understand and comply with study procedures.&#xD;
&#xD;
        Exclusion Criteria- iC9-CAR19 Cell Infusion&#xD;
&#xD;
          -  Subjects meeting any of the following criteria cannot be enrolled in this study:&#xD;
&#xD;
          -  Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically&#xD;
             necessary (e.g., to treat CRS).&#xD;
&#xD;
          -  Severe systemic uncontrolled disease or toxicities that develop after lymphodepletion&#xD;
             may prompt exclusion from cell infusion at the discretion of the investigator.&#xD;
&#xD;
          -  Received any donor lymphocyte infusions (DLI) ≤6 weeks prior to iC9-CAR19 T cell&#xD;
             product administration.&#xD;
&#xD;
          -  Received any T cell lytic or toxic antibody (e.g. alemtuzumab) ≤8 weeks prior to iC9-&#xD;
             CAR19 T cell product administration (residual lytic levels may destroy the infused&#xD;
             iC9- CAR19 T cells and/or prevent their in vivo expansion).&#xD;
&#xD;
        Inclusion Criteria Prior to Lymphodepletion for the Second Infusion&#xD;
&#xD;
          -  Life expectancy ≥ 12 weeks.&#xD;
&#xD;
          -  Documentation of absence of human anti-mouse antibodies (HAMA). Demonstrate adequate&#xD;
             renal and hepatic function as defined below; all screening labs to be obtained within&#xD;
             72 hours prior to lymphodepletion.&#xD;
&#xD;
        Subject meets at least one of the following criteria:&#xD;
&#xD;
          -  B-cell recovery (defined as absolute CD19+ cell count of &gt;50/μL in the blood or bone&#xD;
             marrow CD19+ B cells ≥0.5% of marrow aspirate cells by flow cytometry) within 6 months&#xD;
             of initial infusion. Subjects who meet this criteria within 6 months of initial&#xD;
             infusion may be started on lymphodepletion at a date later than 6 months from initial&#xD;
             infusion.&#xD;
&#xD;
          -  MRD positive (defined as ≥0.01% as assessed by multi-parameter flow cytometry) with&#xD;
             CD19+ expression at any time after initial infusion.&#xD;
&#xD;
          -  At least 4 weeks have passed since the initial iC9-CAR19 T cell infusion.&#xD;
&#xD;
          -  Subjects have resolved/recovered symptoms from CRS and/or ICANS that developed after&#xD;
             prior iC9-CAR19 T cell infusion.&#xD;
&#xD;
          -  Subjects must have autologous transduced activated T cells that meet the Certificate&#xD;
             of Analysis (CofA) acceptance criteria. The subject must have sufficient available&#xD;
             cells or have sufficient stored peripheral blood to manufacture additional iC9-CAR19 T&#xD;
             cells.&#xD;
&#xD;
        Exclusion Criteria for Lymphodepletion for the Second Infusion&#xD;
&#xD;
        Subjects meeting any of the following criteria cannot receive a second infusion as part of&#xD;
        this study:&#xD;
&#xD;
          -  Pregnant or breastfeeding (Note: breast milk cannot be stored for future use if the&#xD;
             milk is collected while the mother is being treated on study).&#xD;
&#xD;
          -  Has a known additional malignancy that is active and/or progressive requiring&#xD;
             treatment; exceptions include basal cell or squamous cell skin cancer, in situ&#xD;
             cervical or bladder cancer, or other cancer for which the subject has been&#xD;
             disease-free for at least five years.&#xD;
&#xD;
          -  Subjects must not have tumor in a location where enlargement could cause airway&#xD;
             obstruction.&#xD;
&#xD;
          -  Subjects may not have an oxygen requirement as defined by pulse oximetry of &lt;90% on&#xD;
             room air.&#xD;
&#xD;
          -  Patients who are on treatment an active uncontrolled infections with resolution of&#xD;
             signs/symptoms are not excluded. Non-influenza, non-RSV, isolated upper respiratory&#xD;
             infections are not excluded. Other active uncontrolled infections will be excluded.&#xD;
&#xD;
          -  Use of systemic corticosteroids at doses ≥10 mg/day prednisone or its equivalent;&#xD;
             those receiving &lt;10 mg/day may be enrolled at discretion of investigator. (Note:&#xD;
             Corticosteroid use with doses at the discretion of the treating physician are allowed&#xD;
             after procurement up to the beginning of lymphodepletion.).&#xD;
&#xD;
        Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent.&#xD;
&#xD;
        Inclusion Criteria- Second iC9-CAR19 Cell Infusion&#xD;
&#xD;
        Subjects must fulfill all of the following inclusion criteria to receive a second iC9-&#xD;
        CAR19 cell infusion on this study:&#xD;
&#xD;
        Exclusion Criteria- Second iC9-CAR19 Cell Infusion&#xD;
&#xD;
        Subjects meeting any of the following criteria cannot receive a second iC9-CAR19 cell&#xD;
        infusion on this study:&#xD;
&#xD;
          -  Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically&#xD;
             necessary (e.g., to treat CRS).&#xD;
&#xD;
          -  Severe systemic uncontrolled disease or toxicities that develop after lymphodepletion&#xD;
             may prompt exclusion from cell infusion at the discretion of the investigator&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Natalie S Grover, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UNC Lineberger Comprehensive Cancer Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Catherine Cheng</last_name>
    <phone>919-445-4208</phone>
    <email>catherine_cheng@med.unc.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kelly Hoye</last_name>
    <phone>919-445-9676</phone>
    <email>kelly_hoye@med.unc.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Catherine Cheng</last_name>
      <phone>919-445-4208</phone>
      <email>catherine_cheng@med.unc.edu</email>
    </contact>
    <contact_backup>
      <last_name>Kelly Hoye</last_name>
      <phone>919-445-9676</phone>
      <email>kelly_hoye@med.unc.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Natalie Grover, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://unclineberger.org/patientcare/clinical-trials/clinical-trials</url>
    <description>Related Info</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 6, 2017</study_first_submitted>
  <study_first_submitted_qc>January 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 10, 2017</study_first_posted>
  <last_update_submitted>September 13, 2023</last_update_submitted>
  <last_update_submitted_qc>September 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CAR T cells</keyword>
  <keyword>CD19</keyword>
  <keyword>Leukemia</keyword>
  <keyword>T Lymphocytes</keyword>
  <keyword>AP1903</keyword>
  <keyword>Cytokine Release Syndrome</keyword>
  <keyword>Rimiducid</keyword>
  <keyword>ICANS</keyword>
  <keyword>Immune effector cell mediated neurotoxicity syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Immune System Diseases</mesh_term>
    <mesh_term>Immunoproliferative Disorders</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/NCT03016377
org study id: LCCC1541-ATL
nct id: NCT03016377
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The body has different ways of fighting infection and disease. No single way is effective at
      fighting cancer. This research study combines two different ways of fighting disease:
      antibodies and T cells. Antibodies are proteins that protect the body from disease caused by
      bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which
      stops them from growing and causing bad effects. T cells, also called T lymphocytes, are
      special infection-fighting blood cells that can kill other cells, including tumor cells or
      cells that are infected. Both antibodies and T cells have been used to treat patients with
      cancers. They both have shown promise, but neither alone has been sufficient to cure most
      patients. This study combines both T cells and antibodies to try to create a more effective
      treatment. This investigational treatment is called autologous T lymphocyte chimeric antigen
      receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration.

      In previous studies, it has been shown that a new gene can be put into T cells that will
      increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes
      make up the chemical structure carrying the genetic information that may determine human
      characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells
      makes a piece of an antibody called anti-CD19. This antibody can flow through the blood and
      can find and stick to leukemia cells because these leukemia cells have a substance on their
      surface called CD19. Anti-CD19 antibodies have been used to treat people with leukemia but
      have not been strong enough to cure most patients. For this study, the anti-CD19 antibody has
      been changed so that instead of floating free in the blood a piece of it is now joined to the
      surface of the T cells. Only the part of the antibody that sticks to the leukemia cells is
      attached to the T cells instead of the entire antibody. When an antibody is joined to a T
      cell in this way it is called a chimeric receptor. These CD19 chimeric (combination)
      receptor-activated T cells kill some of the tumor, but they do not last very long in the body
      and so their chances of fighting the cancer are unknown.

      Preliminary results of giving ATLCAR.CD19 cells to leukemia patients have been encouraging;
      however, many subjects receiving this treatment have experienced unwanted side effects
      including neurotoxicity and/or cytokine release syndrome (also referred to as cytokine storm
      or an infusion reaction). Cytokines are small proteins that interreact as e signals to other
      cells and are the way cells talk to one another. During cytokine release syndrome, too many
      cytokines are released and too many cells in your body react to their release. Symptoms
      resulting from cytokine release syndrome vary from flu-like symptoms to more severe side
      effects such as cardiac arrest, multi-system organ failure or death. We predict that about
      50% of patients on this study will experience mild to severe cytokine release syndrome.

      To help reduce cytokine release syndrome symptoms in future patients, a safety switch has
      been added to the ATLCAR.CD19 cells that can cause the cells to become dormant or "go to
      sleep". The safety switch is called inducible caspase 9 or iC9. The modified ATLCAR.CD19
      cells with the safety switch are referred to as iC9-CAR19 cells.

      The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and
      tolerable (there are not too many unwanted effects). Researchers has previously tested
      different doses of the iC9-CAR19. An effective dose that had the least number of unwanted
      side effects in patients was identified. It was planned to test this dose in more patients to
      learn more about its effect in the body. This type of research study is called a dose
      expansion study. It will allow the investigators to collect more information about the effect
      of this dose in treating of certain type of cancer.
LCCC1541-ATL is a Phase I/Phase II dose finding trial to determine if chimeric antigen
      receptor T (CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9
      safety switch can be safely administered to adult and pediatric subjects with relapsed or
      refractory CD19+ acute lymphoblastic leukemia (ALL).

      OUTLINE

      Cell Procurement

      Peripheral blood, up to 300 mL total (in up to 3 collections) will be obtained from subjects
      for cell procurement. In subjects with inadequate lymphocyte count in the peripheral blood, a
      leukopheresis may be performed to isolate sufficient T cells. The parameters for apheresis
      will be up to 2 blood volumes.

      Lymphodepleting Regimen

      Subjects will receive a lymphodepleting regimen of fludarabine 25 mg/m2/day administered IV
      over 30 min for three consecutive days and a single IV dose of cyclophosphamide 900 mg/m2
      administered over 1 hour on the fourth day. If iC9-CAR19 T cell infusion is delayed for >4
      weeks, lymphodepletion may be repeated prior to iC9-CAR19 T cell infusion.

      Administration of iC9-CAR19 T Cells

      Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will
      receive iC9-CAR19 T cells within 2-14 days after completing the pre-conditioning chemotherapy
      regimen. We will administer iC9-CAR19 post lymphodepletion at dose levels specified. A phase
      I trial performed by Lee et al established that 1×106 CAR19+ T cells/kg was safe and
      associated with significant in vivo expansion and we anticipate similar results with
      iC9-CAR19+ T cells.

      Second Cell Infusion Requirements:

      Subjects will be offered a second infusion based on B-cell recovery and MRD status >4 weeks
      after the initial infusion if cells are available or if the subject has sufficient stored
      peripheral blood to manufacture additional iC9-CAR19 T cells.

      Duration of Therapy

      Therapy in LCCC1541-ATL involves 1 infusion of iC9-CAR19 cells. Treatment with one infusion
      will be administered unless:

        -  Subject decides to withdraw from study treatment, or

        -  General or specific changes in the subject's condition render the subject unacceptable
           for further treatment in the judgment of the investigator.

      A second infusion with prior lymphodepletion will be given to subjects enrolled in the
      expansion cohort and to subjects enrolled in the dose escalation cohort once the RP2D is
      reached if they meet the eligibility requirements for lymphodepletion and infusion.
      Specifically, only subjects with the following characteristics will be offered a second
      infusion:

        -  B-cell recovery (defined as absolute CD19+ cell count >50/μL in the blood or bone marrow
           within 6 months of initial infusion AND/OR

        -  MRD positive (defined as ≥0.01% as assessed by multi-parameter flow cytometry) with
           CD19+ expression at any time after the initial infusion.

        -  *Note that subjects who receive dose level 1 in the dose escalation will receive the
           RP2D for their second infusion, if applicable.

      Duration of Follow-up

      Subjects will be followed for up to 15 years after the final iC9-CAR19 T-cell infusion for
      RCR evaluation or until death, whichever occurs first. Subjects removed from study for
      unacceptable adverse events will be followed until resolution or stabilization of the adverse
      event.

      Subjects who receive new therapy (such as hematopoietic stem cell transplant) after a cell
      product administration will still be required to complete abbreviated follow up procedures.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells
time frame: 4 weeks
description: Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).
measure: Incidence of dose limiting toxicity to identify recommended phase 2 dose (RP2D)
time frame: 4 weeks
description: The recommended phase 2 dose of iC9-CAR19 cells in adult and pediatric subjects will be determined maximum dose at which no more than one out of six patients experiences a dose limiting toxicity (DLT). A DLT is defined according to protocol criteria using the NCI CTCAE, ICANS, and CRS criteria. In general, a DLT is any grade 3 or higher event that is at least possibly related to iC9-CAR19 T cells.
measure: Changes in persistence of iC9-CAR19 T cells in vivo
time frame: 15 years
description: Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.
measure: Overall Response Rate (ORR)
time frame: 15 years
description: ORR (Complete Response/Complete Response with incomplete recovery of counts) to first iC9-CAR19 T cell therapy will be determined using National Comprehensive Cancer Network Response Criteria (NCCN) for acute lymphoblastic leukemia. Assessment of minimal residual disease will be included as criterion of response (ie, the percentage of subjects who achieve CRm [defined as minimal residual disease negative complete response] by either flow cytometry or PCR analysis will be determined)
measure: Overall survival after infusion of iC9-CAR19 T cells
time frame: 15 years
description: Overall survival will be measured from the date of administration of first iC9-CAR19 T cells to the date of death.
measure: Event-free survival rate
time frame: 15 years
description: Event free survival rate applies to all subjects and will be measured from the date of administration of first iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from complete response or complete response with incomplete recovery of counts, or death from any cause; subjects not known to have any of these events are censored on the date they were last examined.
measure: Relapse-free survival rate
time frame: 15 years
description: Relapse-free survival rate will apply only to subjects achieving complete response or complete response with incomplete recovery of counts and measured from the date of achievement of a remission until the date of relapse or death from any cause; subjects not known to have relapsed or died at last follow-up are censored on the date they were last examined.
measure: Incidence of patient reported symptoms in adult patients using selected symptoms from the NCI PRO-CTCAE
time frame: 15 years
description: The NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of 78 symptomatic treatment toxicities.
measure: Changes in patient reported physical functions in adult patients
time frame: 15 years
description: Patient reported physical functions in adult patients will be assessed per the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health on a five point Likert scale with higher score indicating better functioning.
measure: Changes in patient reported health-related quality of life in adult patients
time frame: 15 years
description: Patient reported health-related quality of life will be assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health health on a five point Likert scale with higher score indicating better functioning.
measure: Number of participants with adverse events as a measure of safety and tolerability of a second infusion of iC9-CAR19 T cells
time frame: 4 weeks
description: Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).
measure: Rate of measurable residual disease (MRD) clearance in subjects who receive iC9-CAR19 T cells for MRD persistence or MRD-only relapse
time frame: 8 weeks
description: Rate of MRD clearance will be defined as the proportion of subjects who enter MRD-negative complete response (CRm) who are treated with one or two infusions of iC9 CAR19 T cells at the time of being in complete response (CR) or Complete Response with incomplete recovery of counts (CRi), but not CRm.
arm group label: iC9-CAR19 cells
arm group type: Experimental
description: The 3+3 design in adult subjects and an independent study using 3+3 design in pediatric subjects. The starting dose of 5 x 10^5 transduced cells/kg will enroll 3 adult subjects in the initial cohort. If there are no dose limiting toxicities w/in 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x10^6 transduced cells/kg in adults. If there is toxicity in 1/3 patients in the initial cohort, the cohort will be expanded to enroll up to 6 adult patients. If the dose level 1 is determined to be above the tolerated cell dose, de-escalation would occur to dose level -1 where subjects would receive 1 x 10^5 transduced cells/kg. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before administration of iC9-CAR19 T cells.
arm group label: Expansion Cohort Second Administration of iC9-CAR19 cells
arm group type: Experimental
description: After the recommended phase 2 dose (RP2D) of iC9-CAR19 T cells has been determined in adults, up to 18 additional adult subjects will be enrolled in an expansion cohort at the RP2D. In the expansion cohort, subjects will be offered a second infusion of iC9-CAR19 T cells based on B-cell recovery and minimal residual disease (MRD) status. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before second administration of iC9-CAR19 T cells.
Subjects in the expansion cohort who experience ≥grade 2 CRS or ICANS, did not respond to the initial dose of the standard of care treatment will be enrolled in a sub-study of rimiducid.
intervention type: Biological
intervention name: iC9-CAR19 cells
description: Three dose levels are being evaluated: dose level -1 (1 x 10^5), dose level 1 (5 x 10^5), and dose level 2 ( 1x 10^6)
arm group label: Expansion Cohort Second Administration of iC9-CAR19 cells
arm group label: iC9-CAR19 cells
other name: CAR.CD19 T cells
intervention type: Drug
intervention name: Rimiducid
description: Subjects with CRS and ICAN will assign one of two dose levels (DL)s of rimiducid with the standard treatment: 0.05 mg/kg or 0.1 mg/kg for subjects with CRS and 0.01mg/kg or 0.1mg/kg for subjects with ICAN. Subjects will first be enrolled on DL 1 and then enrolled on DL 2, and 0.4mg/kg rimiducid will be given to subjects who did not respond to the initial dose.
arm group label: Expansion Cohort Second Administration of iC9-CAR19 cells
arm group label: iC9-CAR19 cells
other name: AP1903
intervention type: Drug
intervention name: Cyclophosphamide
description: 900 mg/m^2 IV over 1 hour on day 4 of lymphodepleting chemotherapy.
arm group label: Expansion Cohort Second Administration of iC9-CAR19 cells
arm group label: iC9-CAR19 cells
other name: Neosar
intervention type: Drug
intervention name: Fludarabine
description: 25 mg/m^2/day IV over 30 minutes administered for 3 consecutive days.
arm group label: Expansion Cohort Second Administration of iC9-CAR19 cells
arm group label: iC9-CAR19 cells
other name: Fludara
criteria: 
gender: All
minimum age: 3 Years
maximum age: 70 Years
healthy volunteers: No
last name: Natalie S Grover, MD
role: Principal Investigator
affiliation: UNC Lineberger Comprehensive Cancer Center
last name: Catherine Cheng
phone: 919-445-4208
email: catherine_cheng@med.unc.edu
last name: Kelly Hoye
phone: 919-445-9676
email: kelly_hoye@med.unc.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
url: http://unclineberger.org/patientcare/clinical-trials/clinical-trials
description: Related Info
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Immune System Diseases
mesh term: Immunoproliferative Disorders
mesh term: Cyclophosphamide
mesh term: Fludarabine
sharing ipd: No