Clinical Trials /

Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma

NCT01593696

Description:

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 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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Chronic Lymphocytic Leukemia
  • Mature B-Cell Lymphoma/Leukemia
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Anti-CD19 White Blood Cells for Children and Young Adults With B Cell <span class="go-doc-concept go-doc-disease">Leukemia</span> or Lymphoma

Title

  • Brief Title: Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma
  • Official Title: Phase I Study of T Cells Expressing an Anti-CD19 Chimeric Receptor in Children and Young Adults With B Cell Malignancies
  • Clinical Trial IDs

    NCT ID: NCT01593696

    ORG ID: 120112

    NCI ID: 12-C-0112

    Trial Conditions

    ALL

    B Cell Lymphoma

    Leukemia

    Large Cell Lymphoma

    Non-Hodgkin Lymphoma

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    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 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 CD19 antigen have been constructed and
    are in clinical trials at several institutions. In this trial, the POB will utilize a
    chimeric receptor containing the signaling domains of CD28 and CD3-zeta, currently under
    study in the 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 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 CSF of patients. 4) To describe the toxicity of
    administration of anti-CD19-CAR engineered peripheral blood lymphocytes in children and
    young adults with 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 PBMCs. On Day -7, PBMC will be enriched for CD3+ cells and cultured in
    the presence of anti-CD3/-CD28 beads followed by retroviral vector supernatant
    containing the anti-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.

    Trial Arms

    Name Type Description Interventions
    1 Experimental Without high tumor burden
    2 Experimental With high tumor burden

    Eligibility Criteria

    - INCLUSION CRITERIA

    - Patient must have a 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 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 CLIA approved test in
    the Laboratory of Pathology, CCR, NCI, 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 DTM apheresis and Cell Processing Section, DTM.

    - Subjects with the following 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 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 1800 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
    MUGA or cardiac MRI, or fractional shortening greater than or equal to 28% by 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 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 (ALT and 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.

    - 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 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);

    Minimum Eligible Age: 1 Year

    Maximum Eligible Age: 30 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Safety & amp; Feasibility

    Secondary Outcome Measures

    Persistence of Anti-CD19-CAR Tcells

    Antitumor Effects

    Ability to reduce grade 4 CRS to

    Trial Keywords

    CD 19 Expressing B Cells

    B Cell Lymphoma

    ALL

    Anti-CD19 Chimeric Antigen Receptor

    Adoptive Immunotherapy