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
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      Background:

      Chimeric antigen receptors (CAR) that recognize the cluster of differentiation 19(CD19)
      antigen have been constructed and are in clinical trials at several institutions. In this
      trial, the Pediatric Oncology Branch (POB) will utilize a chimeric receptor containing the
      signaling domains of cluster of differentiation 28 (CD28) and cluster of differentiation 3
      (CD3)-zeta, currently under study in the Center for Cancer Research (CCR) in adults, for
      children and young adults with CD19 expressing malignancies.

      In co-cultures with CD19-expressing acute lymphoblastic leukemia cells,
      anti-CD19-CAR-transduced T cells show robust killing, and in xenograft models, can rapidly
      clear CD19- expressing ALL cell lines.

      Objectives:

        1. Primary: To determine the safety and feasibility of administering escalating doses of
           anti-CD19-CAR engineered peripheral blood lymphocytes in two strata (prior allogeneic
           stem cell transplant [SCT] vs. no prior SCT) of children and young adults with B cell
           malignancies following a cyclophosphamide/fludarabine preparative regimen. COMPLETED
           March 2014.

        2. Primary: To determine the safety of administering cells in two groups of children and
           young adults with B-cell malignancies expressing CD19:

             -  Arm 1 - Patients without high-burden disease or patients for whom chemotherapy
                toxicity is a concern will receive standard preparative regimen.

             -  Arm 2 - Patients with high-burden disease who receive standard chemotherapy to
                reduce burden, (defined as patients with ALL who have M3 bone marrow blasts and/or
                presence of peripheral blood blasts on routine complete blood count (CBC), or
                patients with lymphoma).

        3. Primary: To determine the feasibility of administering anti-CD19 CAR transduced T cells
           within 21 days of the target date in children and young adults with B-cell malignancies
           expressing CD19 enrolled on arm 2: Patients with high-burden disease who receive
           standard chemotherapy to reduce burden.

      1) Secondary: 1) To determine if the administration of anti-CD19-CAR engineered peripheral
      blood lymphocytes can mediate antitumor effects in children with B cell high-burden disease
      after standard chemotherapy, or in patients without high-burden disease who receive standard
      preparative regimen. 2) To evaluate the ability of CRS treatment algorithm to reduce the
      incidence of Grade 4 Cytokine Release Syndrome (CRS) to less than or equal to 10% of
      patients. 3) To measure persistence of adoptively-transferred anti-CD19-CAR-transduced T
      cells in the blood, bone marrow and cerebrospinal fluid (CSF) of patients. 4) To describe the
      toxicity of administration of anti-CD19-CAR engineered peripheral blood lymphocytes in
      children and young adults with central nervous system (CNS) disease.

      Eligibility:

      Patients 1-30 years of age, at least 15 kg, with a CD19-expressing B-cell malignancy that has
      recurred after or not responded to one or more standard chemotherapy-containing regimens for
      their malignancy and is deemed incurable by standard therapy. Patients with a history of
      allogeneic stem cell transplant who meet all eligibility criteria are eligible to
      participate.

      Design:

        -  PBMC will be obtained by leukapheresis. Anti-CD19 CAR T cells will be manufactured from
           fresh or frozen peripheral blood mononuclear cells (PBMCs). On Day -7, PBMC will be
           enriched for cluster of differentiation 3 (CD3)+ cells and cultured in the presence of
           anti-CD3/-cluster of differentiation 28 (CD28) beads followed by retroviral vector
           supernatant containing the anti-cluster of differentiation 19 (CD19) CAR. Total culture
           time is approximately 7-14 days.

        -  Patients will be divided into the 2 groups listed above.

      Arm 1: Patients will begin preparative regimen comprising fludarabine 25 mg/m(2) on Days -4,
      -3 and -2 and cyclophosphamide 900 mg/m(2) on day -2.

      Arm 2: Patients with high-disease burden will be treated with intensive standard of care
      chemotherapy to decrease disease burden during cell manufacturing.

        -  All patients: The CD19-CAR cells will be infused on Day 0, with up to a 72h delay
           allowed for fresh cells or a 21 day delay if cells are cryopreserved, if needed for
           resolution of clinical toxicities or to generate adequate cell numbers.

        -  The previously determined maximum tolerated dose (MTD) of 1 X 10(6) will be administered
           intravenously.

        -  Patients will be monitored for toxicity, response and T cell persistence.
    

Intervention name(s): Anti-Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR)
Intervention type(s): Biological
Intervention description(s): Cells extracted, followed by induction chemotherapy before Cluster of Differentiation (CD)19-Chimeric antigen receptor (CAR) infusion (dose escalation.)
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: CD 19 Expressing B Cells; B Cell Lymphoma; ALL; Anti-CD19 Chimeric Antigen Receptor; Adoptive Immunotherapy