<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/NCT03241940</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-41383</org_study_id>
    <secondary_id>NCI-2017-01415</secondary_id>
    <secondary_id>PEDSCCT5007</secondary_id>
    <secondary_id>IRB-41383</secondary_id>
    <nct_id>NCT03241940</nct_id>
  </id_info>
  <brief_title>Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory B Cell Malignancies</brief_title>
  <official_title>Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young 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>
  </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 best dose and side effects of CD19/CD22 chimeric antigen&#xD;
      receptor (CAR) T cells when given together with chemotherapy, and to see how well they work&#xD;
      in treating children or young adults with CD19 positive B acute lymphoblastic leukemia that&#xD;
      has come back or does not respond to treatment. A CAR is a genetically-engineered receptor&#xD;
      made so that immune cells (T cells) can attack cancer cells by recognizing and responding to&#xD;
      the CD19/CD22 proteins. These proteins are commonly found on B acute lymphoblastic leukemia.&#xD;
      Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in&#xD;
      different ways to stop the growth of cancer cells, either by killing the cells, by stopping&#xD;
      them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and&#xD;
      chemotherapy may work better in treating children or young adults with B acute lymphoblastic&#xD;
      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 children and young adults with B-cell&#xD;
      hematologic malignancies following a cyclophosphamide/fludarabine conditioning regimen. The&#xD;
      following dose escalation will be used in two disease groups: 1) children and young adults&#xD;
      with relapsed/refractory low disease burden ALL (&lt; 5% blasts), and 2) children and young&#xD;
      adults with relapsed/refractory high disease burden ALL (≥5% blasts) or lymphoma:&#xD;
&#xD;
        1. Dose Level -1: 3 x 105 transduced T cells/kg (± 20%)&#xD;
&#xD;
        2. Dose Level 1: 1 x 106 transduced T cells/kg (± 20%)&#xD;
&#xD;
        3. Dose Level 2: 3 x 106 transduced T cells/kg (± 20%)&#xD;
&#xD;
        4. Dose Level 3: 1 x 107 transduced T cells/kg (± 20%)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and&#xD;
      young adults with B-acute lymphoblastic leukemia (ALL).&#xD;
&#xD;
      TERTIARY OBJECTIVES:&#xD;
&#xD;
      I. Analyze alterations in early B cell development induced by immune pressure exerted via&#xD;
      CD19/CD22-CAR T cells.&#xD;
&#xD;
      II. Evaluate whether subjects receiving CD19/CD22-CAR T cells relapse with loss or diminished&#xD;
      expression of CD19 and/or CD22, when feasible.&#xD;
&#xD;
      III. Measure persistence of CD19/CD22-CAR T cells in the blood, bone marrow and cerebral&#xD;
      spinal fluid (CSF), and explore correlations between CD19/CD22-CAR T cell properties and CAR&#xD;
      T cell efficacy and persistence.&#xD;
&#xD;
      IV. Establish the utility of chromatin structure and epigenomic technology to characterize&#xD;
      CAR T cell therapies.&#xD;
&#xD;
      V. Explore the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and&#xD;
      young adults with refractory B cell lymphoma in a non-statistical cohort due to expectations&#xD;
      of low accrual.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of CD19/CD22-CAR T cells.&#xD;
&#xD;
      Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2&#xD;
      and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T&#xD;
      cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of&#xD;
      CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may&#xD;
      receive 2 or 3 additional doses of CD19/CD22-CAR T cells.&#xD;
&#xD;
      After completion of study treatment, patients are followed up daily until day 14, twice&#xD;
      weekly until day 28, at 2 and 3 months, every 3 months until month 12, every 6-12 months up&#xD;
      to year 5, and then annually for years 6-15.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 20, 2017</start_date>
  <completion_date type="Anticipated">August 1, 2035</completion_date>
  <primary_completion_date type="Anticipated">August 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>Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined.</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 (COA)</measure>
    <time_frame>10-14 days after apheresis or thawing of cryopreserved peripheral blood mononuclear cell</time_frame>
    <description>The number of subjects which can successfully manufacture the targeted dose number will be determined for each dose cohort.</description>
  </primary_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-CAR T cells</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be analyzed.</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>Frequency of CD22+ expression on lymphoma cells</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will determine site density when possible.</description>
  </other_outcome>
  <other_outcome>
    <measure>Persistence of CD19/CD22 chimeric antigen receptor (CAR) T cells blood, bone marrow, and cerebral spinal fluid (CSF)</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be measured.</description>
  </other_outcome>
  <other_outcome>
    <measure>Relapse with loss or diminished expression of CD19 and/or CD22</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be evaluated when feasible.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>B Acute Lymphoblastic Leukemia</condition>
  <condition>CD19 Positive</condition>
  <condition>Minimal Residual Disease</condition>
  <condition>Philadelphia Chromosome Positive</condition>
  <condition>Recurrent Adult Acute Lymphoblastic Leukemia</condition>
  <condition>Recurrent Childhood Acute Lymphoblastic Leukemia</condition>
  <condition>Refractory Acute Lymphoblastic Leukemia</condition>
  <arm_group>
    <arm_group_label>Treatment (CD19/CD22-CAR T cells, chemotherapy)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. 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)</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)</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)</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)</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)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        1.1 INCLUSION CRITERIA&#xD;
&#xD;
          1. Diagnosis: ALL In view of the PI and the primary oncologist, there must be no&#xD;
             available alternative curative therapies or subject has declined to pursue alternative&#xD;
             therapy; and subjects must be either ineligible for allogeneic stem cell transplant&#xD;
             (SCT), have refused SCT, recurred after SCT, or have disease activity that prohibits&#xD;
             SCT at the time of enrollment.&#xD;
&#xD;
               1. Chemotherapy refractory disease in subjects with B-ALL is defined as progression&#xD;
                  or stable disease after two lines of therapies&#xD;
&#xD;
               2. Recurrence of disease after achieving a complete response (CR).&#xD;
&#xD;
               3. 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;
               4. Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia&#xD;
                  (Ph+ALL) subjects are eligible if they progressed, had stable disease or relapsed&#xD;
                  after two lines of therapy, including tyrosine kinase inhibitors (TKIs).&#xD;
&#xD;
               5. Subjects with recurrence of isolated CNS relapse after achieving complete&#xD;
                  remission (CR); if relapsed with MRD, will require verification of MRD positivity&#xD;
                  on two occasions at least 4 weeks apart.&#xD;
&#xD;
          2. Diagnosis: Lymphoma Subjects with lymphoma must have progressed, had SD, or recurred&#xD;
             after initial treatment regimens that include an anthracycline and an anti CD20&#xD;
             monoclonal antibody. Subjects who relapse ≥12 months after therapy should have&#xD;
             progressed after autologous transplant or been ineligible for autologous transplant.&#xD;
&#xD;
          3. CD19 expression CD19 expression is required at any time since diagnosis. If patient&#xD;
             has received anti-CD19 targeted therapy (i.e. Blinatumomab), then CD19 expression must&#xD;
             be subsequently demonstrated. CD19 expression. must be detected on greater than 50% of&#xD;
             the malignant cells by immunohistochemistry or ≥ 90% by flow cytometry. The choice of&#xD;
             whether to use flow cytometry or immunohistochemistry will be determined by what is&#xD;
             the most easily available tissue sample in each subject. In general,&#xD;
             immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used&#xD;
             for peripheral blood and bone marrow samples.&#xD;
&#xD;
          4. Subjects who have undergone autologous SCT with disease progression or relapse&#xD;
             following SCT will be eligible if all other eligibility criteria are met. Subjects who&#xD;
             have undergone allogeneic SCT will be eligible if, in addition to meeting other&#xD;
             eligibility criteria, they are at least 100 days post-transplant, they have no&#xD;
             evidence of active GVHD and have been without immunosuppressive agents for at least 30&#xD;
             days.&#xD;
&#xD;
          5. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy will be eligible&#xD;
             if &lt; 5% of circulating levels of CD3+ cells express the previous CAR by flow&#xD;
             cytometry.&#xD;
&#xD;
          6. Must have evaluable or measurable disease; subjects with lymphoma must have evaluable&#xD;
             or measurable disease according to the revised IWG Response Criteria for Malignant&#xD;
             Lymphoma[66] must be present. Lesions that have been previously irradiated will be&#xD;
             considered measurable only if progression has been documented following completion of&#xD;
             radiation therapy.&#xD;
&#xD;
          7. 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;
             f. There is no time restriction with regard to prior intrathecal chemotherapy (incl.&#xD;
             steroids) provided there is complete recovery from any acute toxic effects of such; g.&#xD;
             Subjects receiving hydroxyurea may be enrolled provided there has been no increase in&#xD;
             dose for at least 2 weeks prior to starting apheresis; h. Subjects who are on standard&#xD;
             ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine or oral methotrexate)&#xD;
             may be enrolled provided that chemotherapy is discontinued at least 1 week prior to&#xD;
             apheresis.&#xD;
&#xD;
             i. Subjects receiving steroid therapy at physiologic replacement doses (≤ 5 mg/day of&#xD;
             prednisone or equivalent doses of other corticosteroids) only are allowed provided&#xD;
             there has been no increase in dose for at least 2 weeks prior to starting apheresis;&#xD;
             j. For radiation therapy: Radiation therapy must have been completed at least 3 weeks&#xD;
             prior to enrollment, with the exception that there is no time restriction if the&#xD;
             volume of bone marrow treated is less than 10% and also the subject has&#xD;
             measurable/evaluable disease outside the radiation port.&#xD;
&#xD;
          8. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for&#xD;
             clinically non-significant toxicities, such as alopecia, nutritional support measures,&#xD;
             electrolyte abnormalities, or those not impacting the investigator's ability to assess&#xD;
             treatment emergent toxicities)&#xD;
&#xD;
          9. Age Greater than or equal to 1 year of age and less than or equal to 30 years of age&#xD;
             at time of enrollment; must meet parameters for apheresis per institutional&#xD;
             guidelines. NOTE: The first subject in the first dose cohort must be ≥ 18 years of age&#xD;
             if an adult has not been treated at that dose cohort on the companion Stanford&#xD;
             protocol &quot;Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T&#xD;
             Cells in Adults with Recurrent or Refractory B Cell Malignancies&quot; and undergone safety&#xD;
             evaluation at Day 28 without evidence of DLT.&#xD;
&#xD;
         10. Performance Status: Subjects &gt; 10 years of age: Karnofsky ≥ 50%; Subjects ≤ 10 years&#xD;
             of age: Lansky scale ≥ 50% (See Appendix B Section 14.2)&#xD;
&#xD;
         11. Normal Organ and Marrow Function (supportive care is allowed per institutional&#xD;
             standards, i.e. filgrastim, transfusion)&#xD;
&#xD;
               1. ANC ≥750/uL*&#xD;
&#xD;
               2. Platelet count ≥50,000/uL*&#xD;
&#xD;
               3. Absolute lymphocyte count ≥150/uL*&#xD;
&#xD;
               4. Adequate renal, hepatic, pulmonary and cardiac function defined as:&#xD;
&#xD;
                    -  Serum ALT/AST ≤10 ULN (unless elevated ALT/AST is attributed to leukemia or&#xD;
                       lymphoma involvement of the liver, in which case this criterion will be&#xD;
                       waived and not disqualify a patient).&#xD;
&#xD;
                    -  Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert's syndrome.&#xD;
&#xD;
                    -  Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant&#xD;
                       pericardial effusion as determined by an ECHO, and no clinically significant&#xD;
                       ECG findings&#xD;
&#xD;
                    -  No clinically significant pleural effusion&#xD;
&#xD;
                    -  Baseline oxygen saturation &gt;92% on room air at rest&#xD;
&#xD;
                    -  creatinine: within age adjusted normal institutional limits (see table&#xD;
                       below) OR&#xD;
&#xD;
                    -  creatinine clearance ≥60 mL/min/1.73 m2 (as estimated by Cockcroft Gault&#xD;
                       Equation) for subjects with creatinine levels above institutional normal.&#xD;
&#xD;
             Age (Years) Maximum Serum Creatinine (mg/dL)&#xD;
&#xD;
             ≤5 0.8 5 &lt; age ≤ 10 1.0 &gt;10 1.2&#xD;
&#xD;
             * if these cytopenias are not judged by the investigator to be due to underlying&#xD;
             disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not&#xD;
             be excluded because of pancytopenia ≥ Grade 3 if it is due to disease, based on the&#xD;
             results of bone marrow studies.&#xD;
&#xD;
         12. CNS Status&#xD;
&#xD;
               1. Subjects with ALL&#xD;
&#xD;
                  Subjects with the following CNS status are eligible only in the absence of&#xD;
                  neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:&#xD;
&#xD;
                    -  CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on&#xD;
                       cytospin preparation, regardless of the number of WBCs;&#xD;
&#xD;
                    -  CNS 2, defined as presence of &lt; 5/µL WBCs in CSF and cytospin positive for&#xD;
                       blasts, or &gt; 5/µL WBCs but negative by Steinherz/Bleyer algorithm:&#xD;
&#xD;
                         -  CNS 2a: &lt;10/µL RBCs; &lt; 5/µL WBCs and cytospin positive for blasts;&#xD;
&#xD;
                         -  CNS 2b: ≥10/µL RBCs; &lt; 5/µL WBCs and cytospin positive for blasts;&#xD;
&#xD;
                         -  CNS 2c: ≥10/µL RBCs; ≥5/µL WBCs and cytospin positive for blasts but&#xD;
                            negative by Steinherz/Bleyer algorithm.&#xD;
&#xD;
               2. Subjects with lymphoma&#xD;
&#xD;
             Subjects must have no signs or symptoms of CNS disease or detectable evidence of CNS&#xD;
             disease on MRI at the time of screening. Subjects who have previously been treated for&#xD;
             CNS disease and who have the following CNS status will be eligible:&#xD;
&#xD;
               -  CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin&#xD;
                  preparation, regardless of the number of WBCs;&#xD;
&#xD;
               -  CNS 2, defined as presence of &lt; 5/µL WBCs in CSF and cytospin positive for&#xD;
                  blasts, or &gt; 5/µL WBCs but negative by Steinherz/Bleyer algorithm:&#xD;
&#xD;
                    -  CNS 2a: &lt; 10/µL RBCs; &lt; 5/µL WBCs and cytospin positive for blasts;&#xD;
&#xD;
                    -  CNS 2b: ≥ 10/µL RBCs; &lt; 5/µL WBCs and cytospin positive for blasts;&#xD;
&#xD;
                    -  CNS 2c: ≥ 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts but&#xD;
                       negative by Steinherz/Bleyer algorithm.&#xD;
&#xD;
         13. 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;
         14. Contraception Subjects of child-bearing or child-fathering potential must be willing&#xD;
             to practice birth control from the time of enrollment on this study and for four (4)&#xD;
             months after receiving the preparative regimen.&#xD;
&#xD;
             Females of child-bearing potential must have a negative pregnancy test because of the&#xD;
             potentially dangerous/unknown effects on the fetus.&#xD;
&#xD;
         15. Ability to give informed consent. All subjects ≥ 18 years of age must be able to give&#xD;
             informed consent. For subjects &lt;18 years old their legal authorized representative&#xD;
             (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be&#xD;
             included in age appropriate discussion and verbal assent will be obtained for those &gt;&#xD;
             7 years of age, when appropriate.&#xD;
&#xD;
        1.2 EXCLUSION CRITERIA&#xD;
&#xD;
        Subjects meeting any of the following criteria are not eligible for participation in the&#xD;
        study:&#xD;
&#xD;
          1. Recurrent or refractory ALL limited to isolated testicular.&#xD;
&#xD;
          2. Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence of ≥&#xD;
             5/µL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic&#xD;
             lumbar puncture] and/or clinical signs of CNS leukemia).&#xD;
&#xD;
          3. Hyperleukocytosis (≥ 50,000 blasts/µL) or rapidly progressive disease that in the&#xD;
             estimation of the investigator and sponsor would compromise ability to complete study&#xD;
             therapy.&#xD;
&#xD;
          4. History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g.&#xD;
             cervix, bladder, breast) unless disease free for at least 3 years.&#xD;
&#xD;
          5. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or&#xD;
             requiring IV antimicrobials for management. Simple UTI and uncomplicated bacterial&#xD;
             pharyngitis are permitted if responding to active treatment.&#xD;
&#xD;
             Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus&#xD;
             (anti-HCV positive) as the immunosuppression contained in this study will pose&#xD;
             unacceptable risk. A history of hepatitis B or hepatitis C is permitted if the viral&#xD;
             load is undetectable per quantitative PCR and/or nucleic acid testing.&#xD;
&#xD;
          6. CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar&#xD;
             disease, or autoimmune disease with CNS involvement that in the judgment of the&#xD;
             investigator may impair the ability to evaluate neurotoxicity.&#xD;
&#xD;
          7. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or&#xD;
             other clinically significant cardiac disease within 12 months of enrollment, or have&#xD;
             cardiac atrial or cardiac ventricular lymphoma involvement.&#xD;
&#xD;
          8. Subjects receiving anticoagulation therapy.&#xD;
&#xD;
          9. Any medical condition that in the judgement of the principal investigator is likely to&#xD;
             interfere with assessment of safety or efficacy of study treatment&#xD;
&#xD;
         10. History of severe immediate hypersensitivity reaction to any of the agents used in&#xD;
             this study.&#xD;
&#xD;
         11. Women of child-bearing potential who are pregnant or breastfeeding because of the&#xD;
             potentially dangerous effects of the conditioning lymphodepletion chemotherapy on the&#xD;
             fetus or infant. Females who have undergone surgical sterilization or who have been&#xD;
             postmenopausal for at least 2 years are not considered to be of childbearing&#xD;
             potential.&#xD;
&#xD;
         12. 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;
         13. May not have primary immunodeficiency or history of systemic autoimmune disease (e.g.&#xD;
             Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or&#xD;
             requiring systemic immunosuppression/systemic disease modifying agents within the last&#xD;
             2 years.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Crystal Mackall</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Michelle Fujimoto</last_name>
    <phone>650-736-0539</phone>
    <email>mfujimoto@stanford.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Lucile Packard Children's Hospital Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anne Marcy</last_name>
      <phone>650-721-9994</phone>
      <email>acmarcy@stanford.edu</email>
    </contact>
    <investigator>
      <last_name>Crystal L. Mackall</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>August 3, 2017</study_first_submitted>
  <study_first_submitted_qc>August 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 8, 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>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Neoplasm, Residual</mesh_term>
    <mesh_term>Recurrence</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/NCT03241940
org study id: IRB-41383
secondary id: NCI-2017-01415
secondary id: PEDSCCT5007
secondary id: IRB-41383
nct id: NCT03241940
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the best dose and side effects of CD19/CD22 chimeric antigen
      receptor (CAR) T cells when given together with chemotherapy, and to see how well they work
      in treating children or young adults 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 B acute lymphoblastic leukemia.
      Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, 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. Giving CD19/CD22-CAR T cells and
      chemotherapy may work better in treating children or young adults with 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 children and young adults with B-cell
      hematologic malignancies following a cyclophosphamide/fludarabine conditioning regimen. The
      following dose escalation will be used in two disease groups: 1) children and young adults
      with relapsed/refractory low disease burden ALL (< 5% blasts), and 2) children and young
      adults with relapsed/refractory high disease burden ALL (≥5% blasts) or lymphoma:

        1. Dose Level -1: 3 x 105 transduced T cells/kg (± 20%)

        2. Dose Level 1: 1 x 106 transduced T cells/kg (± 20%)

        3. Dose Level 2: 3 x 106 transduced T cells/kg (± 20%)

        4. Dose Level 3: 1 x 107 transduced T cells/kg (± 20%)

      SECONDARY OBJECTIVES:

      I. Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and
      young adults with B-acute lymphoblastic leukemia (ALL).

      TERTIARY OBJECTIVES:

      I. Analyze alterations in early B cell development induced by immune pressure exerted via
      CD19/CD22-CAR T cells.

      II. Evaluate whether subjects receiving CD19/CD22-CAR T cells relapse with loss or diminished
      expression of CD19 and/or CD22, when feasible.

      III. Measure persistence of CD19/CD22-CAR T cells in the blood, bone marrow and cerebral
      spinal fluid (CSF), and explore correlations between CD19/CD22-CAR T cell properties and CAR
      T cell efficacy and persistence.

      IV. Establish the utility of chromatin structure and epigenomic technology to characterize
      CAR T cell therapies.

      V. Explore the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and
      young adults with refractory B cell lymphoma in a non-statistical cohort due to expectations
      of low accrual.

      OUTLINE: This is a dose-escalation study of CD19/CD22-CAR T cells.

      Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2
      and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T
      cells IV over 10-20 minutes on day 0. 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.

      After completion of study treatment, patients are followed up daily until day 14, twice
      weekly until day 28, at 2 and 3 months, every 3 months until month 12, every 6-12 months up
      to year 5, and then annually for years 6-15.
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: Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined.
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 (COA)
time frame: 10-14 days after apheresis or thawing of cryopreserved peripheral blood mononuclear cell
description: The number of subjects which can successfully manufacture the targeted dose number will be determined for each 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-CAR T cells
time frame: Up to 15 years
description: Will be analyzed.
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: Frequency of CD22+ expression on lymphoma cells
time frame: Up to 15 years
description: Will determine site density when possible.
measure: Persistence of CD19/CD22 chimeric antigen receptor (CAR) T cells blood, bone marrow, and cerebral spinal fluid (CSF)
time frame: Up to 15 years
description: Will be measured.
measure: Relapse with loss or diminished expression of CD19 and/or CD22
time frame: Up to 15 years
description: Will be evaluated when feasible.
arm group label: Treatment (CD19/CD22-CAR T cells, chemotherapy)
arm group type: Experimental
description: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. 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)
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)
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)
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)
intervention type: Other
intervention name: Questionnaire Administration
description: Ancillary studies
arm group label: Treatment (CD19/CD22-CAR T cells, chemotherapy)
criteria: 
gender: All
minimum age: 1 Year
maximum age: 30 Years
healthy volunteers: No
last name: Crystal Mackall
role: Principal Investigator
affiliation: Stanford University
last name: Michelle Fujimoto
phone: 650-736-0539
email: mfujimoto@stanford.edu
facility: 
status: Recruiting
contact: 
investigator: 
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: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Neoplasm, Residual
mesh term: Recurrence
mesh term: Philadelphia Chromosome
mesh term: Cyclophosphamide
mesh term: Fludarabine
mesh term: Fludarabine phosphate
sharing ipd: No