Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma
Condition: ALL; B Cell Lymphoma; Leukemia; Large Cell Lymphoma; Non-Hodgkin Lymphoma
MeSH terms: Lymphoma; Leukemia; Lymphoma, B-Cell
Intervention: Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)
Intervention description: Cells extracted, followed by induction chemotherapy before Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) infusion (dose escalation.)
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 53.0
Sex: All
Minimum age: 1 Year
Maximum age: 30 Years
Healthy volunteers: No
Keywords: CD 19 Expressing B Cells; B Cell Lymphoma; ALL; Anti-CD19 Chimeric Antigen Receptor; Adoptive Immunotherapy

Summary:

      Background:

      - Although progress has been made in treating children with B-cell cancers such as leukemia
      or lymphoma, many children do not respond to the standard treatments. One possible treatment
      involves collecting white blood cells called T cells from the person with cancer and
      modifying the cells to attack the B-cell cancer. The cells can then be given back to the
      participant. This study will use T cells that have been modified to attack the cluster of
      differentiation 19 (CD19) protein, which is found on the surface of some B-cell cancers.

      Objectives:

      - To see if anti-CD19 modified white blood cells are a safe and effective treatment for
      children and young adults with advanced B-cell cancer.

      Eligibility:

        -  Children and young adults between 1 and 30 years of age who have B-cell cancer (leukemia
           or lymphoma) that has not responded to standard treatments.

        -  The leukemia or the lymphoma must have the CD19 protein.

        -  There must be adequate organ function.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected. Imaging studies or bone marrow biopsies may be performed
           depending on the type of cancer.

        -  Participants will undergo a process where white blood cells are collected, called
           apheresis. These cells will be modified to contain the anti-CD19 gene.

        -  Participants will have 3 days of chemotherapy to prepare their immune system to accept
           the modified cells.

        -  Participants will receive an infusion of their own modified white blood cells. They will
           remain in the hospital until they have recovered from the treatment.

        -  Participants will have frequent follow-up visits to monitor the outcome of the
           treatment.

        -  If the participant benefits from the treatment, then he/she may have the option for
           another round of treatment.
    

Eligibility criteria:

        -  INCLUSION CRITERIA

          -  Patient must have a cluster of differentiation 19 (CD19)-expressing B cell ALL or
             lymphoma and must have relapsed or refractory disease after at least one standard
             chemotherapy and one salvage regimen. In view of the principal investigator (PI) and
             the primary oncologist, there must be no available alternative curative therapies and
             subjects must be either ineligible for allogeneic stem cell transplant (SCT), have
             refused SCT, or have disease activity that prohibits SCT at this time.

          -  CD19 expression must be detected on greater than 15% of the malignant cells by
             immunohistochemistry or greater than 30% by flow cytometry in a Clinical Laboratory
             Improvement Amendments (CLIA) approved test in the Laboratory of Pathology, Center for
             Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health
             (NIH), or from the referring institution or reference laboratory. The choice of
             whether to use flow cytometry or immunohistochemistry will be determined by what is
             the most easily available tissue sample in each patient. In general
             immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used
             for peripheral blood and bone marrow samples.

          -  Patients must have measurable or evaluable disease at the time of enrollment, which
             may include any evidence of disease including minimal residual disease detected by
             flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis.

          -  Greater than or equal to 1 year of age (and at least 15 kg) and less than or equal to
             30 years of age.

          -  Adequate absolute CD3 count estimated to be required to obtain target cell dose based
             on discussion with Department of Transfusion Medicine (DTM) apheresis and Cell
             Processing Section, DTM.

          -  Subjects with the following central nervous system (CNS) status are eligible only in
             the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve
             palsy:

               -  CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin
                  preparation, regardless of the number of WBCs;

               -  CNS 2, defined as presence of < 5/uL white blood cells (WBCs) in CSF and cytospin
                  positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm

               -  CNS3 with marrow disease who has failed salvage systemic and intensive IT
                  chemotherapy (and therefore not eligible for radiation)

               -  Patients with isolated CNS relapse will be eligible if they have previously been
                  treated with cranial radiation (at least centigray (cGy)).

          -  Ability to give informed consent. For subjects <18 years old their legal guardian must
             give informed consent. Pediatric subjects will be included in age appropriate
             discussion and verbal assent will be obtained for those greater than or equal to 12
             years of age, when appropriate.

          -  Clinical performance status: Patients > 10 years of age: Karnofsky greater than or
             equal to 50%; Patients less than or equal to 10 years of age: Lansky scale greater
             than or equal to 50%. Subjects who are unable to walk because of paralysis, but who
             are upright in a wheelchair will be considered ambulatory for the purpose of
             calculating the performance score.

          -  Patients of child-bearing or child-fathering potential must be willing to practice
             birth control from the time of enrollment on this study and for four months after
             receiving the preparative regimen.

          -  Females of child-bearing potential must have a negative pregnancy test because of the
             potentially dangerous effects on the fetus.

          -  Cardiac function: Left ventricular ejection fraction greater than or equal to 40% by
             multi-gated acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI), or
             fractional shortening greater than or equal to 28% by echocardiogram (ECHO) or left
             ventricular ejection fraction greater than or equal to 50% by ECHO.

          -  Patients with history of allogeneic stem cell transplantation are eligible if at least
             100 days post-transplant, if there is no evidence of active graft versus host disease
             (GVHD) and no longer taking immunosuppressive agents for at least 30 days prior to
             enrollment.

        EXCLUSION CRITERIA

        Subjects meeting any of the following criteria are not eligible for participation in the
        study:

          -  Recurrent or refractory ALL limited to isolated testicular disease.

          -  Hepatic function: Inadequate liver function defined as total bilirubin > 2x upper
             limit of normal (ULN) (except in the case of subjects with documented Gilbert's
             disease > 3x ULN) or transaminase (alanine aminotransferase (ALT) and aspartate
             aminotransferase (AST) > 20x ULN based on age and laboratory specific normal ranges;

          -  Renal function: Greater than age-adjusted normal serum creatinine (see below) and a
             creatinine clearance < 60 mL/min/1.73 m^2.

               -  Age:

                    -  <= 5 yrs (Maximum Serum Creatinine = 0.8 mg/dL)

                    -  5 < age <=10 yrs (Maximum Serum Creatinine =1.0 mg/dL)

                    -  > 10 yrs (Maximum Serum Creatinine = 1.2 mg/dL)

          -  Hematologic function:

               -  Absolute neutrophil count (ANC) < 750/microliter, or platelet count <
                  50,000/microliter, if these cytopenias are not judged by the investigator to be
                  due to underlying disease (i.e. potentially reversible with anti-neoplastic
                  therapy);

               -  A subject will not be excluded because of pancytopenia greater than or equal to
                  Grade 3 if it is due to disease, based on the results of bone marrow studies.

          -  Hyperleukocytosis (greater than or equal to 50,000 blasts/microliter) or rapidly
             progressive disease that in the estimation of the investigator and sponsor would
             compromise ability to complete study therapy;

          -  Pregnant or breast-feeding females;

          -  Recent prior therapy:

               -  Systemic chemotherapy less than or equal to 2 weeks (6 weeks for nitrosoureas) or
                  radiation therapy less than or equal to 3 weeks prior to apheresis;

        Exceptions:

          -  There is no time restriction in regard to prior intrathecal chemotherapy provided
             there is complete recovery from any acute toxic effects of such;

          -  Subjects receiving hydroxyurea may be enrolled provided there has been no increase in
             dose for at least 2 weeks prior to starting apheresis;

          -  Patients who relapse while receiving standard ALL maintenance chemotherapy will not be
             required to have a waiting period before entry onto this study provided they meet all
             other eligibility criteria;

          -  Subjects receiving steroid therapy at physiologic replacement doses only are allowed
             provided there has been no increase in dose for at least 2 weeks prior to starting
             apheresis;

          -  For radiation therapy: Radiation therapy must have been completed at least 3 weeks
             prior to enrollment, with the exception that there is no time restriction if the
             volume of bone marrow treated is less than 10% and also the subject has
             measurable/evaluable disease outside the radiation port.

               -  Other anti-neoplastic investigational agents currently or within 30 days prior to
                  apheresis (i.e. start of protocol therapy);

               -  Subjects must have recovered from the acute side effects of their prior therapy,
                  such that eligibility criteria are met. Cytopenias deemed to be disease-related
                  and not therapy-related are exempt from this exclusion.

                    -  Human immunodeficiency virus/hepatitis B virus/Hepatitis C virus
                       (HIV/HBV/HCV) Infection:

          -  Seropositive for HIV antibody. (Patients with HIV are at increased risk of lethal
             infections when treated with marrow-suppressive therapy. Appropriate studies will be
             undertaken in patients receiving combination antiretroviral therapy in the future
             should study results indicate effectiveness.)

          -  Seropositive for hepatitis C or positive for Hepatitis B surface antigen (HbsAG).

               -  Monoclonal antibody therapy administered within 30 days of the agent prior to
                  apheresis;

               -  Uncontrolled, symptomatic, intercurrent illness including but not limited to
                  infection, congestive heart failure, unstable angina pectoris, cardiac
                  arrhythmia, psychiatric illness, or social situations that would limit compliance
                  with study requirements or in the opinion of the principal investigator (PI)
                  would pose an unacceptable risk to the subject;

               -  Second malignancy other than in situ carcinoma of the cervix, unless the tumor
                  was treated with curative intent at least two years previously and subject is in
                  remission;

               -  History of severe, immediate hypersensitivity reaction attributed to compounds of
                  similar chemical or biologic composition to any agents used in study or in the
                  manufacturing of the cells (i.e. gentamicin);