<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/NCT03233854</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-41382</org_study_id>
    <secondary_id>41382</secondary_id>
    <secondary_id>CCT5001</secondary_id>
    <nct_id>NCT03233854</nct_id>
  </id_info>
  <brief_title>CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells With or Without NKTR-255 in Adults With Recurrent or Refractory B Cell Malignancies</brief_title>
  <official_title>Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells With or Without NKTR-255 in Adults With Recurrent or Refractory B Cell Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Crystal Mackall, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>California Institute for Regenerative Medicine (CIRM)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Stanford 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 phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T&#xD;
      cells when given together with chemotherapy and NKTR-255, and to see how well they work in&#xD;
      treating patients with CD19 positive B acute lymphoblastic leukemia that has come back or&#xD;
      does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune&#xD;
      cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22&#xD;
      proteins. These proteins are commonly found on diffuse large B-cell lymphoma and B acute&#xD;
      lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine&#xD;
      phosphate, work in different ways to stop the growth of cancer cells, either by killing the&#xD;
      cells, by stopping them from dividing, or by stopping them from spreading. NKTR-255 is an&#xD;
      investigational IL-15 receptor agonist designed to boost the immune system's natural ability&#xD;
      to fight cancer. Giving CD19/CD22-CAR T cells and chemotherapy in combination with NKTR-255&#xD;
      may work better in treating patients with diffuse large B-cell lymphoma or B acute&#xD;
      lymphoblastic leukemia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Determine the feasibility of producing CD19/CD22 CAR T cells meeting the established&#xD;
      release criteria.&#xD;
&#xD;
      II. Assess the safety of administering escalating doses of autologous CD19/CD22 CAR T cells&#xD;
      that meet established release specifications in adults with B cell hematologic malignancies&#xD;
      following a cyclophosphamide/fludarabine conditioning regimen.&#xD;
&#xD;
      III. Assess the safety and feasibility of administering repeated doses of NKTR-255&#xD;
      intravenously after CD19/CD22-CAR T cell infusions in adults with ALL using a dose escalation&#xD;
      design.&#xD;
&#xD;
      IV. Determine the recommended phase 2 dose (RP2D) of NKTR-255 when administered following&#xD;
      CD19/CD22-CAR T cell infusion in adults with ALL&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Evaluate the ability of CD19/CD22 CAR T cells to mediate clinical activity in adults with&#xD;
      DLBCL and adults with ALL.&#xD;
&#xD;
      II. Characterize the pharmacokinetics (PK) of NKTR-255 when administered post CD19/CD22 CAR T&#xD;
      cell infusion.&#xD;
&#xD;
      III. Explore the rate of relapse, progression free survival (PFS) and overall survival (OS)&#xD;
      in subjects receiving CD19/CD22 CAR T cells, followed by up to 6 cycles of NKTR-255&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Anticipated">September 1, 2035</completion_date>
  <primary_completion_date type="Anticipated">September 1, 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>Incidence and severity of dose limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/CD22 chimeric antigen receptor (CAR) T cells</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Safety data will be analyzed per standard methods and interpreted descriptively for each dose cohort. Safety data will be summarized for each dose cohort separately and for all dose cohorts combined. Adverse events will be assessed using the CTCAE version 4.03 for type and severity of event. Serious Adverse Events will be summarized for each dose cohort and for all dose cohorts combined. Reasons for discontinuation of study therapy will be tabulated.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum tolerated dose of CD19/CD22 chimeric antigen receptor (CAR) T cells defined as the dose level immediately below the level at which the enrollment is stopped due to a dose limiting toxicity</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rate of successful manufacture and expansion of the CD19/CD22 chimeric antigen receptor (CAR) T cells to satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>In addition to aiming to evaluate up to 6 subjects at a given dose level with respect to toxicity, the number of subjects which can successfully manufacture the targeted dose number will be determined.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From the start of the preparative regimen until death, assessed for up to 15 years</time_frame>
    <description>Will be assessed by dose cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>From the start of the preparative regimen until the documentation of disease progression or death due to any cause, whichever occurs first, assessed for up to 15 years</time_frame>
    <description>Will be assessed by dose cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The ability to achieve a clinical response after administration of CD19/CD22 chimeric antigen receptor (CAR) T cells</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be assessed by the Response Criteria for Lymphoma and the Response Criteria for Acute Lymphoblastic Leukemia.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Alterations in early B cell development induced by immune pressure exerted via CD19/CD22 chimeric antigen receptor (CAR) T cells</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be evaluated.</description>
  </other_outcome>
  <other_outcome>
    <measure>CD19/CD22 chimeric antigen receptor (CAR) T cell properties</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will explore correlations with CAR T cell efficacy and persistence.</description>
  </other_outcome>
  <other_outcome>
    <measure>Establish the utility of chromatin structure and epigenomic technology to characterize chimeric antigen receptor (CAR) T cell therapies</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Investigators will attempt to establish parameters for how best to utilize the technology in CAR research to: establish basis for blood therapeutic monitoring; derive blood biomarkers for prediction of the safety and efficacy of CAR cell therapy; and develop metrics for CAR T product release criteria that can be used during the manufacturing of the product.</description>
  </other_outcome>
  <other_outcome>
    <measure>Frequency of CD22+ expression on leukemia cells</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will correlate with clinical response to CAR T cells.</description>
  </other_outcome>
  <other_outcome>
    <measure>Persistence of CD19/CD22 chimeric antigen receptor (CAR) T cells blood, bone marrow, and cerebral spinal fluid</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be assessed by flow cytometry. Will be analyzed and reported as time from T cell infusion.</description>
  </other_outcome>
  <other_outcome>
    <measure>Relapse with loss or diminished expression of CD19, CD22 and/or NKTR-255</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be evaluated.</description>
  </other_outcome>
  <other_outcome>
    <measure>Immunogenicity of NKTR-255</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be evaluated when administered post CD19/CD22 CAR T cell infusion.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>B Acute Lymphoblastic Leukemia</condition>
  <condition>CD19 Positive</condition>
  <condition>Minimal Residual Disease</condition>
  <condition>Philadelphia Chromosome Positive</condition>
  <arm_group>
    <arm_group_label>Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive cyclophosphamide IV over 60 minutes and fludarabine phosphate IV over 30 minutes on days -5 to -3. Patients then receive CD19/CD22 CAR T cells IV over 10-20 minutes on day 0. On Day 14 after CAR-T, eligible patients will be given NKTR-255 IV over 30 minutes, and it will be repeated every 28 days for up to 6 cycles. Patients that benefited from the first dose of CD19/CD22 CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22 CAR T cells.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Chimeric Antigen Receptor T-Cell Therapy</intervention_name>
    <description>Given CD19/CD22 CAR T cells IV</description>
    <arm_group_label>Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)</arm_group_label>
    <other_name>CAR T-cell therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)</arm_group_label>
    <other_name>(-)-Cyclophosphamide</other_name>
    <other_name>2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate</other_name>
    <other_name>Carloxan</other_name>
    <other_name>Ciclofosfamida</other_name>
    <other_name>Ciclofosfamide</other_name>
    <other_name>Cicloxal</other_name>
    <other_name>Clafen</other_name>
    <other_name>Claphene</other_name>
    <other_name>CP monohydrate</other_name>
    <other_name>CTX</other_name>
    <other_name>CYCLO-cell</other_name>
    <other_name>Cycloblastin</other_name>
    <other_name>Cycloblastine</other_name>
    <other_name>Cyclophospham</other_name>
    <other_name>Cyclophosphamid monohydrate</other_name>
    <other_name>Cyclophosphamidum</other_name>
    <other_name>Cyclophosphan</other_name>
    <other_name>Cyclophosphane</other_name>
    <other_name>Cyclophosphanum</other_name>
    <other_name>Cyclostin</other_name>
    <other_name>Cyclostine</other_name>
    <other_name>Cytophosphan</other_name>
    <other_name>Cytophosphane</other_name>
    <other_name>Cytoxan</other_name>
    <other_name>Fosfaseron</other_name>
    <other_name>Genoxal</other_name>
    <other_name>Genuxal</other_name>
    <other_name>Ledoxina</other_name>
    <other_name>Mitoxan</other_name>
    <other_name>Neosar</other_name>
    <other_name>Revimmune</other_name>
    <other_name>Syklofosfamid</other_name>
    <other_name>WR- 138719</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine Phosphate</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)</arm_group_label>
    <other_name>2-F-ara-AMP</other_name>
    <other_name>9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-</other_name>
    <other_name>Beneflur</other_name>
    <other_name>Fludara</other_name>
    <other_name>SH T 586</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Questionnaire Administration</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>NKTR-255</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        For B acute lymphoblastic leukemia (ALL)&#xD;
&#xD;
          1. Confirmed diagnosis of relapsed or refractory B-cell ALL of one of the following&#xD;
             types:&#xD;
&#xD;
               -  Chemotherapy refractory disease in subjects with B-ALL, defined as progression or&#xD;
                  stable disease after one line of therapy.&#xD;
&#xD;
               -  Recurrence of disease after achieving CR.&#xD;
&#xD;
          2. Subjects with persistent or relapsed minimal residual disease (MRD) (by flow&#xD;
             cytometry, PCR, FISH, or next generation sequencing) require verification of MRD&#xD;
             positivity on two occasions at least 4 weeks apart.&#xD;
&#xD;
          3. Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL)&#xD;
             subjects are eligible if they progressed after receiving a tyrosine kinase inhibitor&#xD;
             (TKI).&#xD;
&#xD;
          4. Subjects with recurrence of isolated CNS relapse after achieving complete remission&#xD;
             (CR); if relapsed with MRD, will require verification of MRD positivity on two&#xD;
             occasions at least 4 weeks apart.&#xD;
&#xD;
          5. CD19 positive expression- CD19 expression is required at any time since diagnosis. If&#xD;
             patient has received anti-CD19 targeted therapy (i.e. Blinatumomab or CD19-CAR T&#xD;
             cells), then CD19 expression must be subsequently demonstrated. CD19 expression may be&#xD;
             detected by immunohistochemistry or by flow cytometry. The choice of whether to use&#xD;
             flow cytometry or immunohistochemistry will be determined by what is the most easily&#xD;
             available tissue sample in each subject. In general, immunohistochemistry will be used&#xD;
             for lymph node biopsies, flow cytometry will be used for peripheral blood and bone&#xD;
             marrow samples.&#xD;
&#xD;
          6. Subjects who have undergone autologous SCT with disease progression or relapse&#xD;
             following SCT are eligible. Subjects who have undergone allogeneic SCT will be&#xD;
             eligible if, in addition to meeting other eligibility criteria, they have elelino&#xD;
             evidence of GVHD and have been without immunosuppressive agents for at least 30 days.&#xD;
&#xD;
          7. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy must be at least&#xD;
             30 days post CAR infusion and may not have eficence of persistnce of CAR T cells in&#xD;
             blood smples (circulating levels of genetically modified cels of &gt;/= 5% by flow&#xD;
             cytometry.&#xD;
&#xD;
          8. Must have evaluable or measurable disease. Lesions that have been previously&#xD;
             irradiated will be considered measurable only if progression has been documented&#xD;
             following completion of radiation therapy.&#xD;
&#xD;
          9. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any&#xD;
             prior systemic therapy at the time the subject is planned for leukapheresis, except&#xD;
             for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5&#xD;
             half-lives.&#xD;
&#xD;
             Exceptions:&#xD;
&#xD;
               1. There is no time restriction with regard to prior intrathecal chemotherapy (incl.&#xD;
                  steroids) provided there is complete recovery from any acute toxic effects;&#xD;
&#xD;
               2. Subjects who are on standard ALL maintenance type chemotherapy (vincristine,&#xD;
                  6-mercaptopurine or oral methotrexate) may be enrolled provided that chemotherapy&#xD;
                  is discontinued at least 1 week or 5 half-lives (whichever is shorter) prior to&#xD;
                  apheresis.&#xD;
&#xD;
               3. Subjects receiving steroid therapy at physiologic replacement doses (≤5 mg/day of&#xD;
                  prednisone or equivalent doses of other corticosteroids) only are allowed&#xD;
                  provided there has been no increase in dose for at least 2 weeks prior to&#xD;
                  starting apheresis;&#xD;
&#xD;
               4. For radiation therapy: Radiation therapy must have been completed at least 3&#xD;
                  weeks prior to apheresis, with the exception that there is no time restriction if&#xD;
                  the volume of bone marrow treated is less than 10% and also the subject has&#xD;
                  measurable/evaluable disease outside the radiation port.&#xD;
&#xD;
         10. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for&#xD;
             clinically non-significant toxicities such as alopecia)&#xD;
&#xD;
         11. Age 18 or older&#xD;
&#xD;
         12. Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or&#xD;
             Karnofsky ≥ 60%&#xD;
&#xD;
         13. Normal Organ and Marrow Function (supportive care is allowed per institutional&#xD;
             standards, i.e. filgrastim, transfusion)&#xD;
&#xD;
               1. ANC ≥ 1000/uL*&#xD;
&#xD;
               2. Platelet count ≥ 50,000/uL*&#xD;
&#xD;
               3. Absolute lymphocyte count ≥ 300/uL*&#xD;
&#xD;
               4. Adequate renal, hepatic, pulmonary and cardiac function defined as:&#xD;
&#xD;
               5. Creatinine ≤ 2 mg/dL or creatinine clearance ≥ 60 mL/min&#xD;
&#xD;
               6. Serum ALT or AST ≤ 5x ULN (Elevated ALT/AST associated with leukemia or lymphoma&#xD;
                  involvement of the liver will not disqualify a subject; only one value required&#xD;
                  for eligibility).&#xD;
&#xD;
               7. Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.&#xD;
&#xD;
               8. Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant&#xD;
                  pericardial effusion as determined by an ECHO, MUGA or Cardiac MRI [performed&#xD;
                  within 180 days or after most recent anthracycline based treatment or mediastinal&#xD;
                  radiation therapy (whichever is most recent)]&#xD;
&#xD;
               9. No clinically significant ECG findings&#xD;
&#xD;
              10. No clinically significant pleural effusion&#xD;
&#xD;
              11. Baseline oxygen saturation &gt; 92% on room air * A subject will not be excluded&#xD;
                  because of cytopenia if it is felt by the investigator to be due to underlying&#xD;
                  leukemia/lymphoma.&#xD;
&#xD;
         14. Subjects with CNS involvement are eligible as long as there are no overt signs or&#xD;
             symptoms that in the evaluation of the investigator would mask or interfere with the&#xD;
             neurological assessment of toxicity.&#xD;
&#xD;
         15. Females of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             (females who have undergone surgical sterilization or who have been postmenopausal for&#xD;
             at least 2 years are not considered to be of childbearing potential)&#xD;
&#xD;
         16. Subjects of child-bearing or child-fathering potential must be willing to practice&#xD;
             birth control from the time of enrollment on this study and for four (4) months after&#xD;
             receiving the preparative lymphodepletion regimen or 1 month after the last dose of&#xD;
             NKTR_255, whichever is later.&#xD;
&#xD;
         17. Ability to give informed consent. Must be able to give informed consent. Subjects&#xD;
             unable to give informed consent will not be eligible for this study.&#xD;
&#xD;
        =ELIGIBILITY TO RECEIVE NKTR-255=&#xD;
&#xD;
          -  Received a CD19/CD22 CAR-T infusion&#xD;
&#xD;
          -  No persisting grade ≥1 CRS or greater than grade 1 fever within 12 hours preceding&#xD;
             NKTR-255 infusion&#xD;
&#xD;
          -  No grade 4 CRS within 96 hours preceding NKTR-255 infusion&#xD;
&#xD;
          -  No persisting grade ≥ 2 neurotoxicity on the day of NKTR-255 infusion&#xD;
&#xD;
          -  No previous grade ≥ 3 neurotoxicity of &gt; 48 hours duration at any time preceding&#xD;
             NKTR-255 infusion&#xD;
&#xD;
          -  ANC ≥ 1000/µL&#xD;
&#xD;
          -  No intervention with tocilizumab and/or dexamethasone within 48 hours preceding&#xD;
             NKTR-255 infusion&#xD;
&#xD;
          -  No active, serious, and uncontrolled infection(s)&#xD;
&#xD;
          -  No contraindications according to the PI's assessment&#xD;
&#xD;
          -  Life expectancy &gt; 30 days&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of other malignancy, unless disease free for at least 3 years. At the&#xD;
             discretion of the Principal Investigator, subjects in remission for 1-2 years prior to&#xD;
             enrollment may be deemed eligible after considering the nature of other malignancy,&#xD;
             likelihood of recurrence during one year following CAR therapy, and impact of prior&#xD;
             treatment on risk of CD19/CD22-CAR T cells. Subjects in remission &lt;1 year are not&#xD;
             eligible.&#xD;
&#xD;
               -  Exception: Nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder,&#xD;
                  breast) is eligible.&#xD;
&#xD;
               -  Hormonal therapy in subjects in remission &gt;1 year will be allowed.&#xD;
&#xD;
          2. Presence of fungal, bacterial, viral, or other infection that is uncontrolled. Simple&#xD;
             UTI and uncomplicated bacterial pharyngitis are permitted if responding to active&#xD;
             treatment.&#xD;
&#xD;
          3. Known history of infection with any of the following:&#xD;
&#xD;
               -  HIV&#xD;
&#xD;
               -  Hepatitis B (HBsAg positive)&#xD;
&#xD;
               -  Hepatitis C virus (anti-HCV positive) A history of hepatitis B or hepatitis C is&#xD;
                  permitted if the viral load is undetectable per quantitative PCR and/or nucleic&#xD;
                  acid testing.&#xD;
&#xD;
          4. Presence of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia,&#xD;
             cerebellar disease, or any autoimmune disease with CNS involvement that in the&#xD;
             judgment of the investigator may impair the ability to evaluate neurotoxicity.&#xD;
&#xD;
          5. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or&#xD;
             other clinically significant cardiac disease within 12 months of enrollment&#xD;
&#xD;
          6. Any medical condition that in the judgement of the investigator is likely to interfere&#xD;
             with assessment of safety or efficacy of study treatment&#xD;
&#xD;
          7. History of severe immediate hypersensitivity reaction to any of the agents used in&#xD;
             this study&#xD;
&#xD;
          8. Women who are pregnant or breastfeeding&#xD;
&#xD;
          9. In the investigator's judgment, the subject is unlikely to complete all&#xD;
             protocol-required study visits or procedures, including follow-up visits, or comply&#xD;
             with the study requirements for participation.&#xD;
&#xD;
         10. Previous treatment with interleukin-2 or interleukin-15.&#xD;
&#xD;
         11. Confirmed diagnosis of relapsed/refractory biphenotypic BT cell ALL&#xD;
&#xD;
         12. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid&#xD;
             arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease&#xD;
             modifying agents within the last 2 years&#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>Lori Muffly, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maria Iglesias</last_name>
    <phone>650-723-4247</phone>
    <email>miglesias@stanford.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Stanford University, School of Medicine</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maria Iglesias</last_name>
      <phone>650-723-4247</phone>
      <email>miglesias@stanford.edu</email>
    </contact>
    <investigator>
      <last_name>David B. Miklos, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Lori Muffly, MD, MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Laura Johnston, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Everett Meyer, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Andrew Rezvani, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Wen Kai Weng, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Matthew Frank, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Wes (Janice) Brown, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sushma Bharadwaj, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Sally Arai, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Robert Lowsky, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Robert Negrin, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Judith Shizuru, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Praveen Shiraz, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Surbhi Sidana, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Melody Smith, MD, MS</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>July 27, 2023</last_update_submitted>
  <last_update_submitted_qc>July 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Crystal Mackall, MD</investigator_full_name>
    <investigator_title>Professor of Pediatrics</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Neoplasm, Residual</mesh_term>
    <mesh_term>Philadelphia Chromosome</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>
    <mesh_term>Fludarabine phosphate</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/NCT03233854
org study id: IRB-41382
secondary id: 41382
secondary id: CCT5001
nct id: NCT03233854
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T
      cells when given together with chemotherapy and NKTR-255, and to see how well they work in
      treating patients with CD19 positive B acute lymphoblastic leukemia that has come back or
      does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune
      cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22
      proteins. These proteins are commonly found on diffuse large B-cell lymphoma and B acute
      lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine
      phosphate, work in different ways to stop the growth of cancer cells, either by killing the
      cells, by stopping them from dividing, or by stopping them from spreading. NKTR-255 is an
      investigational IL-15 receptor agonist designed to boost the immune system's natural ability
      to fight cancer. Giving CD19/CD22-CAR T cells and chemotherapy in combination with NKTR-255
      may work better in treating patients with diffuse large B-cell lymphoma or B acute
      lymphoblastic leukemia.
PRIMARY OBJECTIVES:

      I. Determine the feasibility of producing CD19/CD22 CAR T cells meeting the established
      release criteria.

      II. Assess the safety of administering escalating doses of autologous CD19/CD22 CAR T cells
      that meet established release specifications in adults with B cell hematologic malignancies
      following a cyclophosphamide/fludarabine conditioning regimen.

      III. Assess the safety and feasibility of administering repeated doses of NKTR-255
      intravenously after CD19/CD22-CAR T cell infusions in adults with ALL using a dose escalation
      design.

      IV. Determine the recommended phase 2 dose (RP2D) of NKTR-255 when administered following
      CD19/CD22-CAR T cell infusion in adults with ALL

      SECONDARY OBJECTIVES:

      I. Evaluate the ability of CD19/CD22 CAR T cells to mediate clinical activity in adults with
      DLBCL and adults with ALL.

      II. Characterize the pharmacokinetics (PK) of NKTR-255 when administered post CD19/CD22 CAR T
      cell infusion.

      III. Explore the rate of relapse, progression free survival (PFS) and overall survival (OS)
      in subjects receiving CD19/CD22 CAR T cells, followed by up to 6 cycles of NKTR-255
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence and severity of dose limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/CD22 chimeric antigen receptor (CAR) T cells
time frame: Up to 28 days
description: Safety data will be analyzed per standard methods and interpreted descriptively for each dose cohort. Safety data will be summarized for each dose cohort separately and for all dose cohorts combined. Adverse events will be assessed using the CTCAE version 4.03 for type and severity of event. Serious Adverse Events will be summarized for each dose cohort and for all dose cohorts combined. Reasons for discontinuation of study therapy will be tabulated.
measure: Maximum tolerated dose of CD19/CD22 chimeric antigen receptor (CAR) T cells defined as the dose level immediately below the level at which the enrollment is stopped due to a dose limiting toxicity
time frame: Up to 28 days
description: Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
measure: Rate of successful manufacture and expansion of the CD19/CD22 chimeric antigen receptor (CAR) T cells to satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis
time frame: Up to 15 years
description: In addition to aiming to evaluate up to 6 subjects at a given dose level with respect to toxicity, the number of subjects which can successfully manufacture the targeted dose number will be determined.
measure: Overall survival
time frame: From the start of the preparative regimen until death, assessed for up to 15 years
description: Will be assessed by dose cohort.
measure: Progression free survival
time frame: From the start of the preparative regimen until the documentation of disease progression or death due to any cause, whichever occurs first, assessed for up to 15 years
description: Will be assessed by dose cohort.
measure: The ability to achieve a clinical response after administration of CD19/CD22 chimeric antigen receptor (CAR) T cells
time frame: Up to 15 years
description: Will be assessed by the Response Criteria for Lymphoma and the Response Criteria for Acute Lymphoblastic Leukemia.
measure: Alterations in early B cell development induced by immune pressure exerted via CD19/CD22 chimeric antigen receptor (CAR) T cells
time frame: Up to 15 years
description: Will be evaluated.
measure: CD19/CD22 chimeric antigen receptor (CAR) T cell properties
time frame: Up to 15 years
description: Will explore correlations with CAR T cell efficacy and persistence.
measure: Establish the utility of chromatin structure and epigenomic technology to characterize chimeric antigen receptor (CAR) T cell therapies
time frame: Up to 15 years
description: Investigators will attempt to establish parameters for how best to utilize the technology in CAR research to: establish basis for blood therapeutic monitoring; derive blood biomarkers for prediction of the safety and efficacy of CAR cell therapy; and develop metrics for CAR T product release criteria that can be used during the manufacturing of the product.
measure: Frequency of CD22+ expression on leukemia cells
time frame: Up to 15 years
description: Will correlate with clinical response to CAR T cells.
measure: Persistence of CD19/CD22 chimeric antigen receptor (CAR) T cells blood, bone marrow, and cerebral spinal fluid
time frame: Up to 15 years
description: Will be assessed by flow cytometry. Will be analyzed and reported as time from T cell infusion.
measure: Relapse with loss or diminished expression of CD19, CD22 and/or NKTR-255
time frame: Up to 15 years
description: Will be evaluated.
measure: Immunogenicity of NKTR-255
time frame: Up to 15 years
description: Will be evaluated when administered post CD19/CD22 CAR T cell infusion.
arm group label: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)
arm group type: Experimental
description: Patients receive cyclophosphamide IV over 60 minutes and fludarabine phosphate IV over 30 minutes on days -5 to -3. Patients then receive CD19/CD22 CAR T cells IV over 10-20 minutes on day 0. On Day 14 after CAR-T, eligible patients will be given NKTR-255 IV over 30 minutes, and it will be repeated every 28 days for up to 6 cycles. Patients that benefited from the first dose of CD19/CD22 CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22 CAR T cells.
intervention type: Biological
intervention name: Chimeric Antigen Receptor T-Cell Therapy
description: Given CD19/CD22 CAR T cells IV
arm group label: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)
other name: CAR T-cell therapy
intervention type: Drug
intervention name: Cyclophosphamide
description: Given IV
arm group label: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)
other name: (-)-Cyclophosphamide
other name: 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
other name: Carloxan
other name: Ciclofosfamida
other name: Ciclofosfamide
other name: Cicloxal
other name: Clafen
other name: Claphene
other name: CP monohydrate
other name: CTX
other name: CYCLO-cell
other name: Cycloblastin
other name: Cycloblastine
other name: Cyclophospham
other name: Cyclophosphamid monohydrate
other name: Cyclophosphamidum
other name: Cyclophosphan
other name: Cyclophosphane
other name: Cyclophosphanum
other name: Cyclostin
other name: Cyclostine
other name: Cytophosphan
other name: Cytophosphane
other name: Cytoxan
other name: Fosfaseron
other name: Genoxal
other name: Genuxal
other name: Ledoxina
other name: Mitoxan
other name: Neosar
other name: Revimmune
other name: Syklofosfamid
other name: WR- 138719
intervention type: Drug
intervention name: Fludarabine Phosphate
description: Given IV
arm group label: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)
other name: 2-F-ara-AMP
other name: 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
other name: Beneflur
other name: Fludara
other name: SH T 586
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)
intervention type: Other
intervention name: Questionnaire Administration
description: Ancillary studies
arm group label: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)
intervention type: Drug
intervention name: NKTR-255
description: Given IV
arm group label: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lori Muffly, MD, MS
role: Principal Investigator
affiliation: Stanford University
last name: Maria Iglesias
phone: 650-723-4247
email: miglesias@stanford.edu
facility: 
status: Recruiting
contact: 
investigator: 
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country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Stanford University
investigator full name: Crystal Mackall, MD
investigator title: Professor of Pediatrics
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Neoplasm, Residual
mesh term: Philadelphia Chromosome
mesh term: Cyclophosphamide
mesh term: Fludarabine
mesh term: Fludarabine phosphate
sharing ipd: No