<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/NCT02215967</url>
  </required_header>
  <id_info>
    <org_study_id>140168</org_study_id>
    <secondary_id>14-C-0168</secondary_id>
    <nct_id>NCT02215967</nct_id>
  </id_info>
  <brief_title>Study of T Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma</brief_title>
  <official_title>A Phase I Clinical Trial of T-Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <has_dmc>No</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>
      Background:&#xD;
&#xD;
      - T cells are white blood cells that fight several cancers. One cancer therapy involves&#xD;
      removing a persons' T cells, changing them in a lab, and then returning them to the person.&#xD;
      Researchers want to see if this helps people with multiple myeloma.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To test the safety of giving anti-B-Cell Maturation Antigen T cells to people with multiple&#xD;
      myeloma.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Adults ages 18-70 with multiple myeloma that has not responded to standard therapies.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants may be screened with:&#xD;
&#xD;
        -  Medical history&#xD;
&#xD;
        -  Physical exam&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
        -  Heart tests&#xD;
&#xD;
        -  Bone marrow sample&#xD;
&#xD;
        -  Multiple scans and X-rays&#xD;
&#xD;
        -  Participants will have apheresis. Blood is removed through a needle in an arm. T cells&#xD;
           are removed. The rest of the blood is returned through a needle in the other arm.&#xD;
&#xD;
        -  The cells will be changed in a laboratory.&#xD;
&#xD;
        -  Participants will get 2 chemotherapy drugs over 3 days.&#xD;
&#xD;
        -  Two days later, participants will check into the hospital. They will get an intravenous&#xD;
           (IV) catheter in an arm or chest vein. They will get the T cells through the IV in 1&#xD;
           infusion.&#xD;
&#xD;
        -  After this, participants will stay in the hospital for at least 9 days and stay nearby&#xD;
           for 2 weeks. Then they will have blood tests and see a doctor.&#xD;
&#xD;
        -  Participants will visit the clinic 1, 2, 3, 4, 6, and 12 months after the infusion, then&#xD;
           every 6 months. A bone marrow sample will be taken at the 2-month visit.&#xD;
&#xD;
        -  Participants blood will be collected for several years. Participants will have an annual&#xD;
           physical at National Institutes of Health (NIH) for 5 years after the infusion. Then for&#xD;
           10 years they will answer health questionnaires.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND:&#xD;
&#xD;
        -  Multiple myeloma (MM) is a malignancy of plasma cells.&#xD;
&#xD;
        -  MM is nearly always incurable.&#xD;
&#xD;
        -  T cells can be genetically modified to express chimeric antigen receptors (CARs) that&#xD;
           specifically target malignancy-associated antigens.&#xD;
&#xD;
        -  Autologous T cells genetically modified to express CARs targeting the B-cell antigen&#xD;
           cluster of differentiation 19 (CD19) have caused complete remissions in a small number&#xD;
           of patients with leukemia or lymphoma. These results demonstrate that CAR-expressing T&#xD;
           cells have anti-malignancy activity in humans.&#xD;
&#xD;
        -  B-cell maturation antigen (BCMA) is a protein expressed by normal plasma cells and the&#xD;
           malignant plasma cells of multiple myeloma.&#xD;
&#xD;
        -  BCMA is not expressed by normal cells except for plasma cells and some mature B cells.&#xD;
&#xD;
        -  We have constructed an anti-BCMA CAR that can specifically recognize BCMA-expressing&#xD;
           target cells in vitro and eradicate BCMA-expressing tumors in mice.&#xD;
&#xD;
        -  Anti-BCMA-CAR-expressing T cells have not been previously tested in humans.&#xD;
&#xD;
        -  We hypothesize that anti-BCMA-CAR-expressing T cells will specifically eliminate&#xD;
&#xD;
      BCMA-expressing MM cells in patients&#xD;
&#xD;
      -Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and&#xD;
      neurological toxicities. Elimination of normal plasma cells and unknown toxicities are also&#xD;
      possible.&#xD;
&#xD;
      OBJECTIVES:&#xD;
&#xD;
      Primary&#xD;
&#xD;
      -Determine the safety and feasibility of administering T cells expressing an anti- BCMA CAR&#xD;
      to patients with MM.&#xD;
&#xD;
      Secondary&#xD;
&#xD;
        -  Evaluate the in vivo persistence of anti-BCMA CAR T cells&#xD;
&#xD;
        -  Assess for evidence of anti-myeloma activity by anti-BCMA CAR T cells&#xD;
&#xD;
      ELIGIBILITY&#xD;
&#xD;
        -  Patients must have measurable MM defined as a serum M-protein greater than or equal to&#xD;
           0.4 g/dL or a urine M-protein greater than or equal to 200 mg/24 hours or an involved&#xD;
           serum free light chain (FLC) level greater than or equal to 10 mg/dL (provided FLC ratio&#xD;
           is abnormal) or a biopsy-proven plasmacytoma.&#xD;
&#xD;
        -  Patients must have previously received at least 3 different treatment regimens for MM.&#xD;
&#xD;
        -  Patients must have a normal creatinine and a normal cardiac ejection fraction.&#xD;
&#xD;
        -  An Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2 is required.&#xD;
&#xD;
        -  Patients on any anticoagulant medications except aspirin are not eligible.&#xD;
&#xD;
        -  No active infections are allowed.&#xD;
&#xD;
        -  Absolute neutrophil count greater than or equal to 1000/ L, platelet count greater than&#xD;
           or equal to 45,000/ L, hemoglobin greater than or equal to 8g/dL&#xD;
&#xD;
        -  Alanine aminotransferase (ALT) and aspartate transaminase (AST) less than or equal to&#xD;
           2.5-fold higher than the upper limit of normal&#xD;
&#xD;
        -  At least 14 days must elapse between the time of any prior systemic treatment (including&#xD;
           corticosteroids) and the required leukapheresis.&#xD;
&#xD;
        -  At least 14 days must elapse between the time of any prior systemic treatment (including&#xD;
           corticosteroids) and initiation of protocol treatment.&#xD;
&#xD;
        -  Bone marrow plasma cells must be 30% or less of total bone marrow cells 30 days or less&#xD;
           prior to the start of protocol treatment.&#xD;
&#xD;
        -  The patient's MM will need to be assessed for BCMA expression by flow cytometry or&#xD;
           immunohistochemistry performed at the National Institutes of Health (NIH). If unstained,&#xD;
           paraffinembedded bone marrow or plasmacytoma sections are available from prior biopsies,&#xD;
           these can be used to determine BCMA expression by immunohistochemistry; otherwise&#xD;
           patients will need to come to the NIH for a bone marrow biopsy or other biopsy of a&#xD;
           plasmacytoma to determine BCMA expression. The sample for BCMA expression can come from&#xD;
           a biopsy obtained at any time before enrollment.&#xD;
&#xD;
      DESIGN:&#xD;
&#xD;
        -  This is a phase I dose-escalation trial&#xD;
&#xD;
        -  Patients will undergo leukapheresis&#xD;
&#xD;
        -  T-cells obtained by leukapheresis will be genetically modified to express an anti- BCMA&#xD;
           CAR&#xD;
&#xD;
        -  Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the&#xD;
           intent of enhancing the activity of the infused anti-BCMA-CAR-expressing T cells.&#xD;
&#xD;
        -  The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m^2 daily for 3 days&#xD;
           and fludarabine 30 mg/m^2 daily for 3 days. Fludarabine will be given on the same days&#xD;
           as the cyclophosphamide.&#xD;
&#xD;
        -  Two days after the chemotherapy ends, patients will receive an infusion of anti-&#xD;
           BCMA-CAR-expressing T cells.&#xD;
&#xD;
        -  The initial dose level of this dose-escalation trial will be 0.3x10^6 CAR+ T cells/kg of&#xD;
           recipient bodyweight.&#xD;
&#xD;
        -  The cell dose administered will be escalated until a maximum tolerated dose is&#xD;
           determined for patients in which less than 50% of total bone marrow cells are plasma&#xD;
           cells.&#xD;
&#xD;
      With Amendment C, all patients with 50% or greater bone marrow plasma cells will receive&#xD;
      3x10(6) anti-BCMA CAR T cells/kg.&#xD;
&#xD;
        -  Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to&#xD;
           monitor for toxicity.&#xD;
&#xD;
        -  Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 4, 6, 9, and 12 months after&#xD;
           the CAR T-cell infusion.&#xD;
&#xD;
        -  Repeat treatments are possible for patients with residual MM and no greater than grade 2&#xD;
           toxicity with an initial treatment.&#xD;
&#xD;
        -  Re-enrollment will be allowed for a small number of subjects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 12, 2014</start_date>
  <completion_date type="Actual">August 15, 2019</completion_date>
  <primary_completion_date type="Actual">April 25, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <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 Dose Limiting Toxicities</measure>
    <time_frame>After the start of treatment and up to 60 days</time_frame>
    <description>Dose limiting toxicities are defined as follows: Grade 3 toxicities possibly or probably related to either the anti-BCMA CAR T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 days. Grade 4 toxicities possibly or probably related to the study interventions.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)</measure>
    <time_frame>Date treatment consent signed to date off study, approx. 3 mos and 7 days for DL 0.3 x 10^6 CAR + T cells, 4 mos and 4 days for 1.0 x 10^6 CAR + T cells, 9 mos and 13 days for 3.0 x 10^6 CAR + T cells, and 48 mos and 12 days for 9.0 x 10^6 CAR + T cells.</time_frame>
    <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Best Response</measure>
    <time_frame>From start of treatment up to 84 weeks</time_frame>
    <description>Best response was assessed by the International Myeloma Working Group response criteria. Partial Remission (PR) is 50% or greater reduction of serum M-protein and 90% or greater reduction in 24-h urinary M-protein. Progressive Disease (PD) is increases of greater or equal to 25% from the lowest post-treatment (nadir) value in serum M-component or urine component or percentage of bone marrow plasma cells. Definite development of new bone lesions or new plasmacytoma. Very Good Partial Remission (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis. Stringent Complete Remission (sCR) is normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry. Complete Remission is negative immunofixation on the serum and urine. Stable Disease (SD) is not meeting criteria for CR, VGPR, PR or PD.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Myeloma, Plasma-Cell</condition>
  <condition>Myeloma-Multiple</condition>
  <arm_group>
    <arm_group_label>Multiple Myeloma</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3</description>
    <arm_group_label>Multiple Myeloma</arm_group_label>
    <other_name>Cytoxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3</description>
    <arm_group_label>Multiple Myeloma</arm_group_label>
    <other_name>Fludara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells</intervention_name>
    <description>0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
    <arm_group_label>Multiple Myeloma</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        2.1.1.1 Multiple Myeloma criteria&#xD;
&#xD;
          -  Clear B-cell maturation antigen (BCMA) expression must be detected on greater than 50%&#xD;
             of malignant plasma cells from either bone marrow or a plasmacytoma by flow cytometry&#xD;
             or immunohistochemistry. These assays must be performed at the National Institutes of&#xD;
             Health. It is not required that the specimen used for BCMA determination comes from a&#xD;
             sample that was obtained after the patient's most recent treatment. BCMA expression&#xD;
             will need to be documented on the majority of malignant plasma cells at some time&#xD;
             after the original anti-BCMA chimeric antigen receptor (CAR) T-cell infusion in all&#xD;
             patients undergoing a second anti-BCMA CAR T-cell infusion. If paraffin embedded&#xD;
             unstained samples of bone marrow involved with multiple myeloma (MM) or a plasmacytoma&#xD;
             are available, these can be shipped to the National Institutes of Health (NIH) for&#xD;
             BCMA staining, otherwise new biopsies will need to be performed for determination of&#xD;
             BCMA expression.&#xD;
&#xD;
          -  Bone marrow plasma cells must make up 30% or less of total bone marrow cells based on&#xD;
             a bone marrow biopsy performed within 30 days of the start of protocol treatment.&#xD;
&#xD;
          -  Patients must have received at least 3 different prior treatment regimens for multiple&#xD;
             myeloma&#xD;
&#xD;
          -  Patients must have measurable MM as defined by at least one of the criteria below.&#xD;
&#xD;
             a. One or more of these abnormalities defines measurable disease:&#xD;
&#xD;
               -  Serum M-protein greater or equal to 1 g/dl (10 g/l).&#xD;
&#xD;
               -  Urine M-protein greater or equal to 200 mg/24 h.&#xD;
&#xD;
               -  Serum free light chain (FLC) assay: involved FLC level greater or equal to10&#xD;
                  mg/dl (100 mg/l) provided serum FLC ratio is abnormal.&#xD;
&#xD;
               -  A biopsy-proven plasmacytoma&#xD;
&#xD;
          -  Patients must have multiple myeloma that meets the criteria for one of the following&#xD;
             Disease categories: (1) progressive disease or (2) relapse from Complete Remission&#xD;
             (CR) as described in the International Uniform Response Criteria for Multiple Myeloma&#xD;
             and as listed below.&#xD;
&#xD;
               1. Progressive Disease (which requires 1 or more of the following)(A):&#xD;
&#xD;
                  Increase of greater than or equal to 25% from the lowest response value (nadir)&#xD;
                  in any one or more of these parameters:&#xD;
&#xD;
                    1. Serum M-component (the absolute increase must be greater than or equal to&#xD;
                       0.5 g/dL) (B) and/or&#xD;
&#xD;
                    2. Urine M-component and/or (the absolute increase must be greater than or&#xD;
                       equal to 200 mg/24 h)&#xD;
&#xD;
                    3. Only in patients without measurable serum and urine M-protein levels; the&#xD;
                       difference between involved and uninvolved FLC levels. The absolute increase&#xD;
                       must be &gt; 10 mg/dL.&#xD;
&#xD;
                    4. Bone marrow plasma cell percentage; the absolute percentage must be greater&#xD;
                       than or equal to 10%&#xD;
&#xD;
          -  Definite development of new bone lesions or soft tissue plasmacytomas or definite&#xD;
             increase in the size of existing bone lesions or soft tissue plasmacytomas (defined as&#xD;
             50% or greater increase in the sum of the products of the cross-diameters of target&#xD;
             lesions)&#xD;
&#xD;
          -  Development of hypercalcemia (corrected serum calcium &gt; 11.5 mg/dL or 2.65 mmol/L)&#xD;
             that can be attributed solely to the plasma cell proliferative disorder&#xD;
&#xD;
             2. Relapse from complete remission (A)&#xD;
&#xD;
          -  Defined as one or more of the following; must be attributable to myeloma:&#xD;
&#xD;
               1. Reappearance of serum or urine M-protein by immunofixation or electrophoresis&#xD;
&#xD;
               2. Development of greater than or equal to 5% plasma cells in the bone marrow&#xD;
&#xD;
               3. Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone&#xD;
                  lesion, or hypercalcemia)&#xD;
&#xD;
        (A)All relapse and progression categories require two consecutive assessments made at any&#xD;
        time before classification as relapse or disease progression and/or the institution of any&#xD;
        new therapy.&#xD;
&#xD;
        (B)For progressive disease, serum M-component increases of greater than or equal to 1 gm/dL&#xD;
        are sufficient to define progression if starting M-component is greater than or equal to 5&#xD;
        g/dL.&#xD;
&#xD;
        2.1.1.2 Other inclusion criteria:&#xD;
&#xD;
          -  Greater than or equal to 18 years of age and less than or equal to age 73.&#xD;
&#xD;
          -  Able to understand and sign the Informed Consent Document.&#xD;
&#xD;
          -  Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0-2&#xD;
&#xD;
          -  Patients of both genders must be willing to practice birth control from the time of&#xD;
             enrollment on this study and for four months after receiving the preparative regimen.&#xD;
&#xD;
          -  Women of child bearing potential must have a negative pregnancy test because of the&#xD;
             potentially dangerous effects of the preparative chemotherapy on the fetus.&#xD;
&#xD;
          -  Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental&#xD;
             treatment being evaluated in this protocol depends on an intact immune system.&#xD;
             Patients who are HIV seropositive can have decreased immune -competence and thus are&#xD;
             less responsive to the experimental treatment and more susceptible to its toxicities.)&#xD;
&#xD;
          -  Seronegative for hepatitis B antigen, positive hepatitis B tests can be further&#xD;
             evaluated by confirmatory tests, and if confirmatory tests are negative, the patient&#xD;
             can be enrolled.&#xD;
&#xD;
          -  Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C antibody&#xD;
             test is positive, then patients must be tested for the presence of antigen by Reverse&#xD;
             transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV)&#xD;
             ribonucleic acid (RNA) negative.&#xD;
&#xD;
          -  Absolute neutrophil count greater than or equal to 1000/mm^3 without the support of&#xD;
             filgrastim or other growth factors.&#xD;
&#xD;
          -  Platelet count greater than or equal to 45,000/mm^3 without transfusion support&#xD;
&#xD;
          -  Hemoglobin greater than 8.0 g/dl.&#xD;
&#xD;
          -  Less than 5% plasma cells in the peripheral blood leukocytes&#xD;
&#xD;
          -  Serum alanine transaminase (ALT) and aspartate transaminase (AST) less or equal to 2.5&#xD;
             times the upper limit of the institutional normal.&#xD;
&#xD;
          -  Serum creatinine less than or equal to 1.3 mg/dL.&#xD;
&#xD;
          -  Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's&#xD;
             Syndrome who must have a total bilirubin less than 3.0 mg/dl.&#xD;
&#xD;
          -  At least 14 days must have elapsed since any prior systemic therapy at the time the&#xD;
             patient starts the cyclophosphamide and fludarabine conditioning regimen, and patients&#xD;
             toxicities must have recovered to a grade 1 or less (except for toxicities such as&#xD;
             alopecia or vitiligo).&#xD;
&#xD;
          -  Because this protocol requires collection of autologous blood cells by leukapheresis&#xD;
             in order to prepare anti-BCMA-CAR T cells, systemic anti-myeloma therapy including&#xD;
             systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or&#xD;
             equivalent dose of another corticosteroid are not allowed within 2 weeks prior to the&#xD;
             required leukapheresis.&#xD;
&#xD;
          -  Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography)&#xD;
             and no evidence of hemodynamically significant pericardial effusion as determined by&#xD;
             an echocardiogram within 6 weeks of the start of the treatment protocol.&#xD;
&#xD;
          -  Patients should not take corticosteroids including prednisone, dexamethasone or any&#xD;
             other corticosteroid for any purpose at doses higher than 5 mg/day of prednisone or&#xD;
             equivalent dose of another corticosteroid 2 weeks before apheresis and within 2 weeks&#xD;
             prior to CAR T-cell infusion, and at any time after the CAR T cell infusion.&#xD;
&#xD;
        2.1.2 EXCLUSION CRITTERIA:&#xD;
&#xD;
          -  Patients on any anticoagulants except aspirin are not eligible.&#xD;
&#xD;
          -  Patients that require urgent therapy due to tumor mass effects or spinal cord&#xD;
             compression.&#xD;
&#xD;
          -  Patients that have active hemolytic anemia.&#xD;
&#xD;
          -  Patients with second malignancies in addition to multiple myeloma are not eligible if&#xD;
             the second malignancy has required treatment within the past 3 years or is not in&#xD;
             complete remission. There are two exceptions to this criterion: successfully treated&#xD;
             non-metastatic basal cell or squamous cell skin carcinoma.&#xD;
&#xD;
          -  Women of child-bearing potential who are pregnant or breastfeeding because of the&#xD;
             potentially dangerous effects of the preparative chemotherapy on the fetus or infant.&#xD;
&#xD;
          -  Active systemic infections (defined as infections causing fevers or requiring&#xD;
             antimicrobial treatment), active coagulation disorders or other major uncontrolled&#xD;
             medical illnesses of the cardiovascular, respiratory, endocrine, renal,&#xD;
             gastrointestinal, genitourinary or immune system, history of myocardial infarction,&#xD;
             active cardiac arrhythmias, active obstructive or restrictive pulmonary disease.&#xD;
&#xD;
          -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency&#xD;
             Disease).&#xD;
&#xD;
          -  Systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or&#xD;
             equivalent dose of another corticosteroid are not allowed within 2 weeks prior to&#xD;
             either the required leukapheresis or the initiation of the conditioning chemotherapy&#xD;
             regimen.&#xD;
&#xD;
          -  History of severe immediate hypersensitivity reaction to any of the agents used in&#xD;
             this study.&#xD;
&#xD;
          -  History of allogeneic stem cell transplantation&#xD;
&#xD;
          -  Patients with central nervous system (CNS) metastases or symptomatic CNS involvement&#xD;
             (including cranial neuropathies or mass lesions and spinal cord compression).&#xD;
&#xD;
          -  Patients with active autoimmune skin diseases such as psoriasis or other active&#xD;
             autoimmune diseases such as rheumatoid arthritis.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>73 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>James N Kochenderfer, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-C-0168.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013 May;10(5):267-76. doi: 10.1038/nrclinonc.2013.46. Epub 2013 Apr 2.</citation>
    <PMID>23546520</PMID>
  </reference>
  <reference>
    <citation>Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, Gress RE, Hakim FT, Kochenderfer JN. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013 Apr 15;19(8):2048-60. doi: 10.1158/1078-0432.CCR-12-2422. Epub 2013 Jan 23.</citation>
    <PMID>23344265</PMID>
  </reference>
  <reference>
    <citation>Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012 Mar 22;119(12):2709-20. doi: 10.1182/blood-2011-10-384388. Epub 2011 Dec 8.</citation>
    <PMID>22160384</PMID>
  </reference>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>August 12, 2014</study_first_submitted>
  <study_first_submitted_qc>August 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2014</study_first_posted>
  <results_first_submitted>August 26, 2019</results_first_submitted>
  <results_first_submitted_qc>September 20, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">October 8, 2019</results_first_posted>
  <last_update_submitted>September 20, 2019</last_update_submitted>
  <last_update_submitted_qc>September 20, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cancer Institute (NCI)</investigator_affiliation>
    <investigator_full_name>James Kochenderfer, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Immunotherapy</keyword>
  <keyword>Anti-BCMA-CAR</keyword>
  <keyword>Gene Therapy</keyword>
  <keyword>Adoptive T Cell Therapy</keyword>
  <keyword>Plasma Cell Malignancy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</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>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 21, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/67/NCT02215967/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 16, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/67/NCT02215967/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>0.3 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="P2">
          <title>1 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="P3">
          <title>3 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="P4">
          <title>9 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="5"/>
                <participants group_id="P4" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Patient became ineligible for treatment</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Patient did not get CAR T-Cells</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>0.3 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="B2">
          <title>1 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="B3">
          <title>3 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="B4">
          <title>9 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="5"/>
            <count group_id="B4" value="19"/>
            <count group_id="B5" value="30"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="17"/>
                    <measurement group_id="B5" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58.93" spread="4.87"/>
                    <measurement group_id="B2" value="54.0" spread=".71"/>
                    <measurement group_id="B3" value="55.76" spread="5.65"/>
                    <measurement group_id="B4" value="54.13" spread="6.86"/>
                    <measurement group_id="B5" value="56.49" spread="5.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="7"/>
                    <measurement group_id="B5" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="14"/>
                    <measurement group_id="B5" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="15"/>
                    <measurement group_id="B5" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="19"/>
                    <measurement group_id="B5" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Dose Limiting Toxicities</title>
        <description>Dose limiting toxicities are defined as follows: Grade 3 toxicities possibly or probably related to either the anti-BCMA CAR T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 days. Grade 4 toxicities possibly or probably related to the study interventions.</description>
        <time_frame>After the start of treatment and up to 60 days</time_frame>
        <population>One participant in Group 9x10(6) did not get CAR T-cells and was deemed ineligible, and 3 participants in Group 9x10(6) were found to be ineligible for treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>0.3 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O2">
            <title>1 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O3">
            <title>3 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O4">
            <title>9 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Dose Limiting Toxicities</title>
          <description>Dose limiting toxicities are defined as follows: Grade 3 toxicities possibly or probably related to either the anti-BCMA CAR T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 days. Grade 4 toxicities possibly or probably related to the study interventions.</description>
          <population>One participant in Group 9x10(6) did not get CAR T-cells and was deemed ineligible, and 3 participants in Group 9x10(6) were found to be ineligible for treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Hypophosphatemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Confusion</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dyspnea (intubated)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ejection fraction decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Encephalopathy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypoxia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Acute kidney injury (CVVH)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sepsis (Staph Aureus)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Muscle weakness lower limbs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Muscle weakness upper limbs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Platelet count decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neutrophil count decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Acute kidney injury</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypotension</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CPK increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Musculoskeletal/connective tissue disorders-Rhabd.</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)</title>
        <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
        <time_frame>Date treatment consent signed to date off study, approx. 3 mos and 7 days for DL 0.3 x 10^6 CAR + T cells, 4 mos and 4 days for 1.0 x 10^6 CAR + T cells, 9 mos and 13 days for 3.0 x 10^6 CAR + T cells, and 48 mos and 12 days for 9.0 x 10^6 CAR + T cells.</time_frame>
        <population>One participant in Group 9x10(6) did not get CAR T-cells and was deemed ineligible, and 3 participants in Group 9x10(6) were found to be ineligible for treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>0.3 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O2">
            <title>1 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O3">
            <title>3 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O4">
            <title>9 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)</title>
          <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
          <population>One participant in Group 9x10(6) did not get CAR T-cells and was deemed ineligible, and 3 participants in Group 9x10(6) were found to be ineligible for treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Best Response</title>
        <description>Best response was assessed by the International Myeloma Working Group response criteria. Partial Remission (PR) is 50% or greater reduction of serum M-protein and 90% or greater reduction in 24-h urinary M-protein. Progressive Disease (PD) is increases of greater or equal to 25% from the lowest post-treatment (nadir) value in serum M-component or urine component or percentage of bone marrow plasma cells. Definite development of new bone lesions or new plasmacytoma. Very Good Partial Remission (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis. Stringent Complete Remission (sCR) is normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry. Complete Remission is negative immunofixation on the serum and urine. Stable Disease (SD) is not meeting criteria for CR, VGPR, PR or PD.</description>
        <time_frame>From start of treatment up to 84 weeks</time_frame>
        <population>One participant in Group 9x10(6) did not get CAR T-cells and was deemed ineligible, and 3 participants in Group 9x10(6) were found to be ineligible for treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>0.3 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O2">
            <title>1 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O3">
            <title>3 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
          <group group_id="O4">
            <title>9 x 10^6 CAR-BCMA T-cells Infused</title>
            <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Best Response</title>
          <description>Best response was assessed by the International Myeloma Working Group response criteria. Partial Remission (PR) is 50% or greater reduction of serum M-protein and 90% or greater reduction in 24-h urinary M-protein. Progressive Disease (PD) is increases of greater or equal to 25% from the lowest post-treatment (nadir) value in serum M-component or urine component or percentage of bone marrow plasma cells. Definite development of new bone lesions or new plasmacytoma. Very Good Partial Remission (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis. Stringent Complete Remission (sCR) is normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry. Complete Remission is negative immunofixation on the serum and urine. Stable Disease (SD) is not meeting criteria for CR, VGPR, PR or PD.</description>
          <population>One participant in Group 9x10(6) did not get CAR T-cells and was deemed ineligible, and 3 participants in Group 9x10(6) were found to be ineligible for treatment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Partial Remission</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Very Good Partial Remission</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Complete Remission</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stringent Complete Remission</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Date treatment consent signed to date off study, approximately 3 months and 7 days for dose level 0.3 x 10^6 CAR + T cells, 4 months and 4 days for 1.0 x 10^6 CAR + T cells, 9 months and 13 days for 3.0 x 10^6 CAR + T cells, and 48 months and 12 days for 9.0 x 10^6 CAR + T cells.</time_frame>
      <desc>One participant in Group 9x10(6) did not get CAR T-cells and was deemed ineligible, and 3 participants in Group 9x10(6) were found to be ineligible for treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>0.3 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="E2">
          <title>1 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="E3">
          <title>3 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
        <group group_id="E4">
          <title>9 x 10^6 CAR-BCMA T-cells Infused</title>
          <description>Dose Escalation with 5 dose levels based on the patients actual bodyweight&#xD;
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3&#xD;
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3&#xD;
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="11" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Disseminated intravascular coagulation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="5" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Supraventricular tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="5" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypothermia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections and infestations - Other, CMV viremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, Salmonella</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="3" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>CPK increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="5" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Cardiac troponin T increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="4" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="4" subjects_affected="4" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Acidosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Muscle weakness upper limb</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, Rhabdomyalysis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="3" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Delirium</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="7" subjects_affected="5" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="5" subjects_affected="3" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="6" subjects_affected="5" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="16" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" events="7" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" events="42" subjects_affected="13" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT corrected interval prolonged</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="6" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="14" subjects_affected="11" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="15" subjects_affected="12" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="36" subjects_affected="15" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="11" subjects_affected="7" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypothermia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Surgical and medical procedures - Other, specify</sub_title>
                <description>Basal cell carcinoma removal (face and upper back)</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="11" subjects_affected="8" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Catheter related infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, Clostridium difficile stool</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, Clostridium difficile</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="9" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="7" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" events="10" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" events="49" subjects_affected="14" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="13" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="12" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" events="14" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" events="68" subjects_affected="16" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" events="5" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" events="58" subjects_affected="11" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="14" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="14" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" events="18" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" events="69" subjects_affected="16" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="9" subjects_affected="7" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Acidosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Alkalosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="6" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="8" subjects_affected="6" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="4" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="5" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Fibrinogen decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="8" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>INR increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="9" subjects_affected="7" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" events="5" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" events="59" subjects_affected="14" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>CPK increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="4" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="31" subjects_affected="15" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="4" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="3" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="18" subjects_affected="10" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify</sub_title>
                <description>Basal cell carcinoma (L base of neck)</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify</sub_title>
                <description>Basal cell carcinoma (L cheek)</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify</sub_title>
                <description>Basal cell carcinoma (upper back)</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="4" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Delirium</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="7" subjects_affected="4" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="5" subjects_affected="5" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="5" subjects_affected="5" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="9" subjects_affected="7" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. James N. Kochenderfer</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>240-760-6062</phone>
      <email>kochendj@mail.nih.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02215967
org study id: 140168
secondary id: 14-C-0168
nct id: NCT02215967
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - T cells are white blood cells that fight several cancers. One cancer therapy involves
      removing a persons' T cells, changing them in a lab, and then returning them to the person.
      Researchers want to see if this helps people with multiple myeloma.

      Objective:

      - To test the safety of giving anti-B-Cell Maturation Antigen T cells to people with multiple
      myeloma.

      Eligibility:

      - Adults ages 18-70 with multiple myeloma that has not responded to standard therapies.

      Design:

        -  Participants may be screened with:

        -  Medical history

        -  Physical exam

        -  Blood and urine tests

        -  Heart tests

        -  Bone marrow sample

        -  Multiple scans and X-rays

        -  Participants will have apheresis. Blood is removed through a needle in an arm. T cells
           are removed. The rest of the blood is returned through a needle in the other arm.

        -  The cells will be changed in a laboratory.

        -  Participants will get 2 chemotherapy drugs over 3 days.

        -  Two days later, participants will check into the hospital. They will get an intravenous
           (IV) catheter in an arm or chest vein. They will get the T cells through the IV in 1
           infusion.

        -  After this, participants will stay in the hospital for at least 9 days and stay nearby
           for 2 weeks. Then they will have blood tests and see a doctor.

        -  Participants will visit the clinic 1, 2, 3, 4, 6, and 12 months after the infusion, then
           every 6 months. A bone marrow sample will be taken at the 2-month visit.

        -  Participants blood will be collected for several years. Participants will have an annual
           physical at National Institutes of Health (NIH) for 5 years after the infusion. Then for
           10 years they will answer health questionnaires.
BACKGROUND:

        -  Multiple myeloma (MM) is a malignancy of plasma cells.

        -  MM is nearly always incurable.

        -  T cells can be genetically modified to express chimeric antigen receptors (CARs) that
           specifically target malignancy-associated antigens.

        -  Autologous T cells genetically modified to express CARs targeting the B-cell antigen
           cluster of differentiation 19 (CD19) have caused complete remissions in a small number
           of patients with leukemia or lymphoma. These results demonstrate that CAR-expressing T
           cells have anti-malignancy activity in humans.

        -  B-cell maturation antigen (BCMA) is a protein expressed by normal plasma cells and the
           malignant plasma cells of multiple myeloma.

        -  BCMA is not expressed by normal cells except for plasma cells and some mature B cells.

        -  We have constructed an anti-BCMA CAR that can specifically recognize BCMA-expressing
           target cells in vitro and eradicate BCMA-expressing tumors in mice.

        -  Anti-BCMA-CAR-expressing T cells have not been previously tested in humans.

        -  We hypothesize that anti-BCMA-CAR-expressing T cells will specifically eliminate

      BCMA-expressing MM cells in patients

      -Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and
      neurological toxicities. Elimination of normal plasma cells and unknown toxicities are also
      possible.

      OBJECTIVES:

      Primary

      -Determine the safety and feasibility of administering T cells expressing an anti- BCMA CAR
      to patients with MM.

      Secondary

        -  Evaluate the in vivo persistence of anti-BCMA CAR T cells

        -  Assess for evidence of anti-myeloma activity by anti-BCMA CAR T cells

      ELIGIBILITY

        -  Patients must have measurable MM defined as a serum M-protein greater than or equal to
           0.4 g/dL or a urine M-protein greater than or equal to 200 mg/24 hours or an involved
           serum free light chain (FLC) level greater than or equal to 10 mg/dL (provided FLC ratio
           is abnormal) or a biopsy-proven plasmacytoma.

        -  Patients must have previously received at least 3 different treatment regimens for MM.

        -  Patients must have a normal creatinine and a normal cardiac ejection fraction.

        -  An Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2 is required.

        -  Patients on any anticoagulant medications except aspirin are not eligible.

        -  No active infections are allowed.

        -  Absolute neutrophil count greater than or equal to 1000/ L, platelet count greater than
           or equal to 45,000/ L, hemoglobin greater than or equal to 8g/dL

        -  Alanine aminotransferase (ALT) and aspartate transaminase (AST) less than or equal to
           2.5-fold higher than the upper limit of normal

        -  At least 14 days must elapse between the time of any prior systemic treatment (including
           corticosteroids) and the required leukapheresis.

        -  At least 14 days must elapse between the time of any prior systemic treatment (including
           corticosteroids) and initiation of protocol treatment.

        -  Bone marrow plasma cells must be 30% or less of total bone marrow cells 30 days or less
           prior to the start of protocol treatment.

        -  The patient's MM will need to be assessed for BCMA expression by flow cytometry or
           immunohistochemistry performed at the National Institutes of Health (NIH). If unstained,
           paraffinembedded bone marrow or plasmacytoma sections are available from prior biopsies,
           these can be used to determine BCMA expression by immunohistochemistry; otherwise
           patients will need to come to the NIH for a bone marrow biopsy or other biopsy of a
           plasmacytoma to determine BCMA expression. The sample for BCMA expression can come from
           a biopsy obtained at any time before enrollment.

      DESIGN:

        -  This is a phase I dose-escalation trial

        -  Patients will undergo leukapheresis

        -  T-cells obtained by leukapheresis will be genetically modified to express an anti- BCMA
           CAR

        -  Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the
           intent of enhancing the activity of the infused anti-BCMA-CAR-expressing T cells.

        -  The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m^2 daily for 3 days
           and fludarabine 30 mg/m^2 daily for 3 days. Fludarabine will be given on the same days
           as the cyclophosphamide.

        -  Two days after the chemotherapy ends, patients will receive an infusion of anti-
           BCMA-CAR-expressing T cells.

        -  The initial dose level of this dose-escalation trial will be 0.3x10^6 CAR+ T cells/kg of
           recipient bodyweight.

        -  The cell dose administered will be escalated until a maximum tolerated dose is
           determined for patients in which less than 50% of total bone marrow cells are plasma
           cells.

      With Amendment C, all patients with 50% or greater bone marrow plasma cells will receive
      3x10(6) anti-BCMA CAR T cells/kg.

        -  Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to
           monitor for toxicity.

        -  Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 4, 6, 9, and 12 months after
           the CAR T-cell infusion.

        -  Repeat treatments are possible for patients with residual MM and no greater than grade 2
           toxicity with an initial treatment.

        -  Re-enrollment will be allowed for a small number of subjects.
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Dose Limiting Toxicities
time frame: After the start of treatment and up to 60 days
description: Dose limiting toxicities are defined as follows: Grade 3 toxicities possibly or probably related to either the anti-BCMA CAR T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 days. Grade 4 toxicities possibly or probably related to the study interventions.
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
time frame: Date treatment consent signed to date off study, approx. 3 mos and 7 days for DL 0.3 x 10^6 CAR + T cells, 4 mos and 4 days for 1.0 x 10^6 CAR + T cells, 9 mos and 13 days for 3.0 x 10^6 CAR + T cells, and 48 mos and 12 days for 9.0 x 10^6 CAR + T cells.
description: Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
measure: Number of Participants With Best Response
time frame: From start of treatment up to 84 weeks
description: Best response was assessed by the International Myeloma Working Group response criteria. Partial Remission (PR) is 50% or greater reduction of serum M-protein and 90% or greater reduction in 24-h urinary M-protein. Progressive Disease (PD) is increases of greater or equal to 25% from the lowest post-treatment (nadir) value in serum M-component or urine component or percentage of bone marrow plasma cells. Definite development of new bone lesions or new plasmacytoma. Very Good Partial Remission (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis. Stringent Complete Remission (sCR) is normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry. Complete Remission is negative immunofixation on the serum and urine. Stable Disease (SD) is not meeting criteria for CR, VGPR, PR or PD.
arm group label: Multiple Myeloma
arm group type: Experimental
description: Dose Escalation with 5 dose levels based on the patients actual bodyweight
intervention type: Drug
intervention name: Cyclophosphamide
description: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3
arm group label: Multiple Myeloma
other name: Cytoxan
intervention type: Drug
intervention name: Fludarabine
description: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3
arm group label: Multiple Myeloma
other name: Fludara
intervention type: Biological
intervention name: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells
description: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0
arm group label: Multiple Myeloma
criteria: 
gender: All
minimum age: 18 Years
maximum age: 73 Years
healthy volunteers: No
last name: James N Kochenderfer, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-C-0168.html
description: NIH Clinical Center Detailed Web Page
citation: Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013 May;10(5):267-76. doi: 10.1038/nrclinonc.2013.46. Epub 2013 Apr 2.
PMID: 23546520
citation: Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, Gress RE, Hakim FT, Kochenderfer JN. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013 Apr 15;19(8):2048-60. doi: 10.1158/1078-0432.CCR-12-2422. Epub 2013 Jan 23.
PMID: 23344265
citation: Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012 Mar 22;119(12):2709-20. doi: 10.1182/blood-2011-10-384388. Epub 2011 Dec 8.
PMID: 22160384
responsible party type: Principal Investigator
investigator affiliation: National Cancer Institute (NCI)
investigator full name: James Kochenderfer, M.D.
investigator title: Principal Investigator
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Cyclophosphamide
mesh term: Fludarabine
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 