Clinical Trials /

CAR T Cell Receptor Immunotherapy for Patients With B-cell Lymphoma

NCT00924326

Description:

Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with B cell lymphomas or leukemias that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-cluster of differentiation 19 (CD19) incorporated in the retrovirus. Objective: The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-CD19 cells) cause tumors to shrink. Eligibility: - Adults age 18-70 with B cell lymphomas or leukemias expressing the CD19 molecule. Design: Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-CD19 cells. Leukapheresis is a common procedure, which removes only the white blood cells from the patient. Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy and the anti-CD19 cells. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

Related Conditions:
  • Mature B-Cell Lymphoma/Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

CAR T Cell Receptor <span class="go-doc-concept go-doc-intervention">Immunotherapy</span> for Patients With B-cell Lymphoma

Title

  • Brief Title: CAR T Cell Receptor Immunotherapy for Patients With B-cell Lymphoma
  • Official Title: Assessment of the Safety and Feasibility of Administering T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor to Patients With B-cell Lymphoma
  • Clinical Trial IDs

    NCT ID: NCT00924326

    NCT Alias ID: NCT00862069

    ORG ID: 090082

    NCI ID: 09-C-0082

    Trial Conditions

    Primary Mediastinal B-cell Lymphoma

    Diffuse, Large B-cell Lymphoma

    Trial Interventions

    Drug Synonyms Arms
    Fludarabine Single Arm
    Cyclophosphamide Single Arm

    Trial Purpose

    Background:

    The NCI Surgery Branch has developed an experimental therapy for treating patients with B
    cell lymphomas or leukemias that involves taking white blood cells from the patient, growing
    them in the laboratory in large numbers, genetically modifying these specific cells with a
    type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to
    the patient. This type of therapy is called gene transfer. In this protocol, we are
    modifying the patient s white blood cells with a retrovirus that has the gene for
    anti-CD19 incorporated in the retrovirus.

    Objective:

    The purpose of this study is to determine a safe number of these cells to infuse and to see
    if these particular tumor-fighting cells (anti-CD19 cells) cause tumors to shrink.

    Eligibility:

    - Adults age 18-68 with B cell lymphomas or leukemias expressing the CD19 molecule.

    Design:

    Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo
    a history and physical examination, scans, x-rays, lab tests, and other tests as needed

    Leukapheresis: If the patients meet all of the requirements for the study they will undergo
    leukapheresis to obtain white blood cells to make the anti-CD19 cells. {Leukapheresis is a
    common procedure, which removes only the white blood cells from the patient.}

    Treatment: Once their cells have grown, the patients will be admitted to the hospital for
    the conditioning chemotherapy and the anti-CD19 cells. They will stay in the hospital for
    about

    4 weeks for the treatment.

    Follow up: Patients will return to the clinic for a physical exam, review of side effects,
    lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
    year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

    ...

    Detailed Description

    BACKGROUND:

    - We have constructed a retroviral vector that encodes an anti-CD19 chimeric antigen
    receptor (CAR) that recognizes the CD19 antigen. This chimeric receptor also contains
    the signaling domains of CD28 and CD3-zeta. The retroviral vector can be used to
    mediate genetic transfer of this CAR to T cells with high efficiency (> 50%) without
    the need to perform any selection.

    - In co-cultures with CD19-expressing target cells, anti-CD19-CAR-transduced T cells
    secreted significant amounts of IFN-y and IL-2.

    - We have developed a process for cryopreserving the cell product which may lead to the
    ability for this product to be manufactured at a central location and shipped to other
    institutions for treatment of a broader patient population

    OBJECTIVES:

    - Primary objectives

    - With the approval of amendment S, determine the safety and feasibility of the
    administration of cryopreserved anti-CD19-CAR engineered peripheral blood lymphocytes
    with a nonmyeloablative conditioning regimen in patients with B-cell malignancies.

    - Secondary objectives:

    - With the approval of amendment S, determine the in vivo survival of the cryopreserved
    anti-CD19-CAR-transduced T cells.

    - Determine if the treatment regimen can cause regression of B-cell malignancies.

    ELIGIBILITY:

    Patients of 18 years of age or older must:

    - have a CD19-expressing B-cell malignancy of any type

    - be a non-responder to, or recurred after one or more standard chemotherapy-containing
    regimens for their malignancy

    - currently require treatment due to progressive malignancy

    - deemed to be incurable by standard therapy

    Patients may not have:

    - a history of allogeneic stem cell transplantation

    - CNS disease

    DESIGN:

    - PBMC obtained by leukapheresis (approximately 5 X 109 cells) will be cultured in the
    presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell proliferation.

    - Transduction is initiated by exposure of approximately 108 to 5 X 108 cells to
    retroviral vector supernatant containing the anti-CD19 CAR.

    - With the approval of amendment S, patients will receive fludarabine and
    cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion, followed by cryopreserved
    anti-CD19-CAR-transduced T cells.

    - Patients will be followed until disease progression

    - Patients who have responded to treatment and then progress may receive one retreatment

    Trial Arms

    Name Type Description Interventions
    Single Arm Experimental Patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion followed by anti-CD19- CAR-transduced T cells Fludarabine, Cyclophosphamide

    Eligibility Criteria

    - INCLUSION CRITERIA:

    1. Patient must have a CD19-expressing B cell malignancy. Patients with Diffuse
    large B-cell lymphoma, Primary Mediastinal B-cell lymphoma, and Diffuse large
    B-cell lymphoma transformed from follicular lymphoma must have measurable
    disease after at least two prior chemotherapy regimens one of which must have
    contained doxorubicin and rituximab.

    2. Confirmation of diagnosis of B cell malignancy and positivity for CD19 confirmed
    by the Laboratory of Pathology of the NCI. 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. Immunohistochemistry will be used for
    lymph node biopsies, flow Cytometry will be used for peripheral blood, fine
    needle aspirates and bone marrow samples.

    3. Patients must have indications for treatment for their B cell malignancy at the
    time of enrollment on this trial.

    4. Greater than or equal to 18 years of age and less than or equal to age 70.

    5. Willing to sign a durable power of attorney.

    6. Able to understand and sign the Informed Consent Document.

    7. Clinical performance status of ECOG 0 or 1.

    8. Life expectancy of greater than three months.

    9. Patients of both genders must be willing to practice birth control from the time
    of enrollment on this study and for four months after treatment.

    10. Women of child bearing potential must have a negative pregnancy test because of
    the potentially dangerous effects of the treatment on the fetus.

    11. Serology:

    - 1. Seronegative for HIV antibody. (The experimental treatment being
    evaluated in this protocol depends on an intact immune system. Patients who
    are HIV seropositive can have decreased immune -competence and thus be less
    responsive to the experimental treatment and more susceptible to its
    toxicities.).

    - 2. Seronegative for hepatitis B antigen and hepatitis C antibody unless
    antigen negative. If hepatitis C antibody test is positive, then patients
    must be tested for the presence of antigen by RT-PCR and be HCV RNA
    negative.

    12. Hematology:

    - 1. Absolute neutrophil count greater than or equal to 1000/mm(3) without
    the support of filgrastim.

    - 2. Platelet count greater than or equal to 50,000/mm(3).

    - 3. Hemoglobin greater than 8.0 g/dl.

    - 4. Lymphocyte count less than or equal to 4,000/ mm(3)

    13. Chemistry:

    - 1. Serum ALT/AST less or equal to 5 times the upper limit of normal.

    - 2. Serum creatinine less than or equal to 1.6 mg/dl

    - 3. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with
    Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl

    14. More than three weeks must have elapsed since any prior systemic therapy at the
    time the patient receives the preparative regimen, and patients toxicities
    must have recovered to a grade 1 or less (except for toxicities such as alopecia
    or vitiligo).

    15. Normal cardiac ejection fraction and no evidence of pericardial effusion as
    determined by an echocardiogram.

    EXCLUSION CRITERIA:

    1. Patients that require urgent therapy due to tumor mass effects such as bowel
    obstruction or blood vessel compression.

    2. Patients that have active hemolytic anemia.

    3. Patients with active brain metastases, or with a history of any CNS metastases or
    cerebrospinal fluid malignant cells.

    Note: patients who are asymptomatic but are found to have malignant cells in the CSF
    on lumbar puncture prior to treatment will be considered eligible.

    4. Women of child-bearing potential who are pregnant or breastfeeding because of the
    potentially dangerous effects of the treatment on the fetus or infant.

    5. Active systemic infections, coagulation disorders or other major medical illnesses of
    the cardiovascular, respiratory or immune system, myocardial infarction, cardiac
    arrhythmias, obstructive or restrictive pulmonary disease.

    6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
    Disease).

    7. Concurrent opportunistic infections (The experimental treatment being evaluated in
    this protocol depends on an intact immune system. Patients who have decreased immune
    competence may be less responsive to the experimental treatment and more

    susceptible to its toxicities).

    8. Concurrent Systemic steroid therapy.

    9. History of severe immediate hypersensitivity reaction to any of the agents used in
    this study.

    10. History of allogeneic stem cell transplantation

    11. Patients with cardiac atrial or cardiac ventricular lymphoma involvement.

    Screening Evaluation:

    Within 4 weeks prior to starting the chemotherapy regimen:

    1. Complete history and physical examination, including, weight and vital signs, noting
    in detail the exact size and location of any lesions that exist. (Note: patient
    history may be obtained within 8 weeks.)

    2. Chest x-ray

    3. EKG

    4. Baseline CT of the chest, abdomen and pelvis, PET scan, and brain MRI to evaluate the
    status of disease. Additional scans and x-rays may be performed if clinically
    indicated based on patients signs and symptoms.

    5. HIV antibody titer and HbsAG determination, and anti HCV, (Note: may be performed
    within 3 months of the chemotherapy start date).

    6. Anti CMV antibody titer, HSV serology, and EBV panel (Note: patients who are known to
    be positive for any of the above do not need to be retested; may be performed within
    3 months of chemotherapy start date)

    7. Patients with a LVEF of less than or equal to 55% will not proceed to treatment,

    (Note: may be performed within 8 weeks of treatment).

    8. CD19 staining of malignant cells by immunohistochemistry or flow cytometry (testing
    is permitted to be conducted at any time prior to this point).

    9. All patients must have a TBNK for Peripheral blood CD3 count and CD19#.

    10. Patients with a history of leptomeningeal disease, or signs/symptoms suggestive of
    leptomeningeal involvement, or with symptoms of central nervous system malignancy
    such as new onset severe headaches, neck stiffness, or any focal neurologic findings
    on physical exam will have lumbar puncture for examination of cerebral spinal fluid.

    11. Patients may undergo lumbar puncture (LP) for flow cytometry of the CSF in order to
    assess the presence of CD19 positive lymphocytes for potential correlation with
    neurologic toxicity. Patients who have no neurologic symptoms at the time of LP

    will be eligible for enrollment regardless of the results of the flow cytometry.

    Within 14 days prior to starting the chemotherapy regimen:

    12. Chem 20: (Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate),
    Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total
    (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin,
    Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid)

    13. Thyroid panel

    14. CBC with differential and platelet count

    15. PT/PTT

    16. Urinalysis and culture, if indicated

    Within 7 days prior to starting the chemotherapy regimen:

    17. <=-HCG pregnancy test (serum or urine) on all women of child-bearing potential

    18. ECOG performance status of 0 or 1

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 70 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Determine the safety and feasibility of the administration of anti-CD19-CAR engineered peripheral blood lymphocytes with a nonmyeloablative conditioning regimen in patients with B-cell malignancies.

    Secondary Outcome Measures

    Trial Keywords

    B Cell Malignancies

    T Cell Persistence

    Immunotherapy

    Cell Transfer

    Leukemia

    Chronic Lymphocytic Leukemia

    CLL

    Lymphoma