Clinical Trials /

T Cells Expressing HER2-specific Chimeric Antigen Receptors(CAR) for Patients With HER2-Positive CNS Tumors

NCT02442297

Description:

This study is for patients that have brain cancer. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting immune cells present in the blood that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. The antibody used in this study is called anti-HER2 (Human Epidermal Growth Factor Receptor 2). This antibody sticks to tumor cells because of a substance on the outside of these cells called HER2. Many types of brain tumors are positive for HER2 . HER2 antibodies have been used to treat people with HER2-positive cancers. For this study, the HER2 antibody has been changed so that instead of floating free in the blood it is now attached to T cells. When an antibody is joined to a T cell in this way it is called a chimeric antigen receptor (CAR). These CAR-T cells seem to be able to kill tumors like the one these patients have, but they don't last very long and so their chances of fighting the cancer are limited. Therefore, developing ways to prolong the life of these T cells should help them fight cancer. These HER2-CAR T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the largest safe dose of HER2-CAR T cells, to learn what the side effects are, and to see whether this experimental intervention might help patients with brain tumors who volunteer to test this new agent.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

T Cells Expressing <span class="go-doc-concept go-doc-biomarker">HER2</span>-specific Chimeric Antigen Receptors(CAR) for Patients With <span class="go-doc-concept go-doc-disease">Glioblastoma</span>

Title

  • Brief Title: T Cells Expressing HER2-specific Chimeric Antigen Receptors(CAR) for Patients With Glioblastoma
  • Official Title: Phase I Study of Intracranial Injection of T Cells Expressing HER2-specific Chimeric Antigen Receptors (CAR) in Subjects With Glioblastoma
  • Clinical Trial IDs

    NCT ID: NCT02442297

    ORG ID: H-31973-iCAR

    Trial Conditions

    Glioblastoma

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    This study is for patients that have a type of brain cancer called Glioblastoma (GBM). The
    body has different ways of fighting infection and disease. No single way seems perfect for
    fighting cancers. This research study combines two different ways of fighting cancer:
    antibodies and T cells. Antibodies are types of proteins that protect the body from
    infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special
    infection-fighting immune cells present in the blood that can kill other cells, including
    cells infected with viruses and tumor cells. Both antibodies and T cells have been used to
    treat patients with cancers. They have shown promise, but have not been strong enough to
    cure most patients.

    The antibody used in this study is called anti-HER2 (Human Epidermal Growth Factor Receptor
    2). This antibody sticks to GBM cells because of a substance on the outside of these cells
    called HER2. Up to 80% of GBMs are positive for HER2 . HER2 antibodies have been used to
    treat people with HER2-positive cancers. For this study, the HER2 antibody has been changed
    so that instead of floating free in the blood it is now attached to T cells. When an
    antibody is joined to a T cell in this way it is called a chimeric antigen receptor (CAR).
    These CAR-T cells seem to be able to kill tumors like the one these patients have, but they
    don't last very long and so their chances of fighting the cancer are limited. Therefore,
    developing ways to prolong the life of these T cells should help them fight cancer.

    These HER2-CAR T cells are an investigational product not approved by the Food and Drug
    Administration.

    The purpose of this study is to find the largest safe dose of HER2-CAR T cells, to learn
    what the side effects are, and to see whether this experimental intervention might help
    patients with GBM who volunteer to test this new agent.

    Detailed Description

    First, to find out if HER2 is expressed in the patient's GBM, the investigators will need to
    obtain the tissue block or tissue specimen that was used to make the original diagnosis. If
    there is enough material, investigators may also look for other proteins that may be targets
    for this sort of immune therapy in the future.

    Up to 90mls (18 tsp) of blood will be drawn on two occasions for a total of 180mls (36tsp).
    The total amount of blood drawn will not be more than 3 ml (less than 1 teaspoon) per 2.2
    lbs of body weight.

    To make HER2 CAR T cells the investigators will introduce the HER2 CAR gene into patient's T
    cells. To get the HER2 antibody to attach to the surface of the T cells, investigators will
    insert the antibody gene into the T cells. This is done with a virus called a retrovirus
    that has been made for this study and will carry the antibody gene into the T cell. This
    virus also helps the investigators find the T cells in patient's blood after they inject
    them. Most of the cells generated will be frozen and stored to give back to the patient.

    This is a dose escalation study. This means that at the beginning, patients will be started
    on the lowest dose (1 of 3 different levels) of T cells. Once that dose schedule proves
    safe, the next group of patients will be started at a higher dose. This process will
    continue until all 3 dose levels are studied. If the side effects are too severe, the dose
    will be lowered or the T-cell infusions will be stopped.

    The patient will be given a single injection of cells into a special catheter that a
    neurosurgeon will implant into the tumor or the cavity left in the brain after surgical
    removal. Before the patient receives the injection, they may be given a dose of Tylenol. The
    injection will take between 1 and 10 minutes. The patient will be admitted for overnight
    observation after the T-cell injection. The injection of T cells will be given by the
    Center for Cell and Gene Therapy at Houston Methodist Hospital.

    If the patient has stable disease (the tumor did not grow) or there is a reduction in the
    size of patient's tumor on imaging studies after the T-cell injection (at least 6 weeks
    after), they can receive additional doses of the T cells at 6 to 12 week intervals if they
    wish. Additional doses of T cells will be given at the current dose being assessed on the
    study. Therefore, the dose the patient receives for additional doses may be higher than the
    initial dose they received.

    Before being treated, the patient will receive a series of standard medical tests:physical
    exam, blood tests to measure blood cells, kidney and liver function,' pregnancy test if the
    patient is a female who could potentially become pregnant or might be pregnant, measurements
    of patient's tumor by routine imaging studies.

    The patient will receive standard medical tests when they are getting the infusions and
    after: physical exams, blood tests to measure blood cells, kidney and liver function,
    measurements of patient's tumor by routine imaging studies 6 weeks after the infusion.

    To learn more about the way the HER2-CAR T cells are working and how long they last in the
    body, an extra amount of blood, based on patient's weight, up to a maximum of 60 mL (12
    teaspoons) of blood will be taken on the day of the T-cell infusion (before and 1 to 4 hours
    after the T-cell infusion), 3-4 days after the infusion (this one is optional), 1, 2, 4 and
    6 weeks after the T-cell infusion and every 3 months for 1 year, every 6 months for 4 years,
    then yearly for a total of 15 years. This volume is considered safe, but may be decreased if
    the patient is anemic. This sample will be kept in a coded manner so that only the study
    staff may identify the patient.

    During the time points listed above, if the T cells are found in patient's blood at a
    certain amount, an extra 5ml of blood may need to be collected for additional testing.

    To see if there are any long-term side effects of gene transfer, the investigators will
    follow the patient up to 15 years.

    If the patient receives additional T-cell infusions after the first one, they will have the
    same tests and blood draws as described above.

    If the patient has a tumor biopsy or lumbar puncture to obtain CSF performed any time while
    they are on the study, a sample of this will be requested for research purposes.

    If the patient develops a second abnormal growth, significant blood or nervous system
    disorder during the trial, a biopsy sample of the tissue will be tested for research
    purposes (if a sample can be obtained).

    Trial Arms

    Name Type Description Interventions
    HER2-specific T cells Experimental

    Eligibility Criteria

    Inclusion criteria at the time of procurement.

    - Recurrent or refractory GBM

    - Subjects having a tumor resection

    - Karnofsky score of greater than or equal to 60

    - Informed consent explained to, understood by and signed by subject/guardian.
    Subject/guardian given copy of informed consent

    Exclusion Criteria at the time of procurement:

    Known HIV positivity

    Treatment Inclusion criteria:

    - Recurrent or refractory HER2-positive* GBM

    * Immunohistochemisty (IHC) or RT-PCR will be used to determine HER2 positivity.
    Results will be compared to standard controls. HER2 expression in tumors on IHC
    should be greater than or equal to grade 2 and greater than or equal to 2+ intensity
    score. Wherein grades are defines as: Grade 0: no staining; Grade 1: 1-25%; Grade 2:
    26-50% and Grade 3: 51-100% of cell staining for HER2 and intensity scores are:
    negative; 1+; 2+ and 3+ using breast cancer standard arrays as a guide for intensity.

    - Intracranial catheter (such as Rickham or Ommaya) in place

    - Age 18 years

    - Life expectancy 6 weeks

    - Karnofsky score 60

    - Bilirubin less than or equal to 3x normal, AST less than or equal to 5x normal, ALT
    less than or equal to 5x, serum creatinine less than or equal to 2x upper limit of
    normal for age, and Hgb greater than or equal to 8.0

    - Pulse oximetry of greater than or equal to 90% on room air

    - Sexually active subjects must be willing to utilize one of the more effective birth
    control methods for 6 months after the T cell infusion. The male partner should use a
    condom

    - Available autologous transduced T lymphocytes with greater than or equal to 15%
    expression of HER2 CAR determined by flow-cytometry and killing of HER2-positive
    targets greater than or equal to 20% in cytotoxicity assay

    - Subjects should have been off other investigational antineoplastic therapy for two
    weeks prior to entry in this study. Temozolomide will be allowed up to 48 hours
    preinfusion. Dexamethasone up to a total dose of 2 mg per day will be allowed if
    medically indicated

    - Informed consent explained to, understood by and signed by research
    subjects/guardian. Subject/guardian given copy of informed consent.

    Treatment Exclusion Criteria:

    - Severe intercurrent infection

    - Known HIV positivity

    - Pregnant or lactating

    - History of hypersensitivity reactions to murine protein-containing products.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Number of patients with dose limiting toxicity after administration of autologous T cells expressing transgenic chimeric antigen receptors (CAR) targeting the HER2 molecule

    Secondary Outcome Measures

    Median amount of HER2-specific T cells in the Patients' Blood

    Number of Patients with a tumor response

    Trial Keywords

    Glioblastoma

    T cells Expressing HER2-specific Chimeric Antigen Receptors

    HER2-specific T cells

    intracranial injection