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:
  • Central Nervous System Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: T Cells Expressing HER2-specific Chimeric Antigen Receptors(CAR) for Patients With HER2-Positive CNS Tumors
  • Official Title: Phase I Study of Intracranial Injection of T Cells Expressing HER2-specific Chimeric Antigen Receptors (CAR) in Subjects With HER2-Positive Tumors of the Central Nervous System (iCAR)

Clinical Trial IDs

  • ORG STUDY ID: H-31973-iCAR
  • NCT ID: NCT02442297

Conditions

  • Brain Tumor, Recurrent
  • Brain Tumor, Refractory

Interventions

DrugSynonymsArms
HER2-specific T cellsDosing Schedules 1, 2, and 3HER2-specific T cells - High Risk

Purpose

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.

Detailed Description

      First, to find out if HER2 is expressed in the patient's brain cancer, 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 dosing schedule (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 schedule. This process
      will continue until all 3 dose schedules 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 three injections of cells two weeks apart into a special catheter
      that a neurosurgeon will implant into the tumor or the cavity left in the brain after
      surgical removal or into the fluid-filled space in your brain. The first injection of cells
      you receive will be the lowest dose. The subsequent injections, depending on the patient's
      assigned dosing schedule, may be higher than the first. Before the patient receives each
      injection, they may be given a dose of Tylenol. Each injection will take between 1 and 10
      minutes. The patient will be admitted for overnight observation after each T-cell injection.
      Injections of T cells will be given by the Center for Cell and Gene Therapy at Texas
      Children's Hospital or Houston Methodist Hospital.

      If the patient has stable disease (the tumor did not grow), a reduction in the size of the
      tumor on imaging studies, or if the patient's disease has progressed but his health status is
      stable after the start of T-cell injections (at least 6 weeks after), they can receive
      additional doses of the T cells at 2 to 4 week intervals if they wish. Additional doses of T
      cells will be given at the highest cell dose the patient receives during the initial three
      cell infusions. 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, s/he 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
      s/he 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

NameTypeDescriptionInterventions
HER2-specific T cells - High RiskExperimentalSubjects with HER2 staining of Grade 3 (51-100% of cells staining for HER2) and intensity scores of 3+ will be assigned to the High Risk arm. Three cell dosing schedules (1, 2, 3) consisting of combinations of three cell doses (A, B, C) will be evaluated.
  • HER2-specific T cells
HER2-specific T cells - Standard RiskExperimentalAll other patients not meeting the high risk description will be assigned to the Standard Risk arm. Three cell dosing schedules (1, 2, 3) consisting of combinations of three cell doses (A, B, C) will be evaluated.
  • HER2-specific T cells

Eligibility Criteria

        Inclusion criteria at the time of procurement.

          -  Recurrent or refractory HER2 positive primary central nervous system (CNS) tumor or
             HER2 positive tumor metastatic to the CNS. Patients in whom tumor resection (gross
             total or subtotal resection) is medically feasible can undergo surgery after
             procurement and prior to treatment.

          -  Subjects having a tumor resection if medically feasible

          -  Karnofsky/Lansky 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:

          -  Diagnosis of DIPG

          -  Bulky tumors causing midline shift and/or symptoms/signs due to impending herniation

          -  Known HIV positivity

        Treatment Inclusion criteria:

          -  Recurrent or refractory HER2-positive* primary CNS tumor or HER2-positive solid tumor
             metastatic to the CNS

             * Immunohistochemistry (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 1 and greater than or equal to 1+ 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 ≥ 3 years

          -  Life expectancy ≥ 6 weeks

          -  Karnofsky/Lansky 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 7.0

          -  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

          -  Patients who have undergone tumor resection should have recovered from the surgery.
             Patients with neurological deficits should have deficits that are stable for minimum
             of 1 week prior to treatment.

          -  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.

          -  Diagnosis of DIPG

          -  Steroid dose of dexamethasone greater than 2 mg per day (or equivalent)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with dose limiting toxicity after administration of autologous T cells expressing transgenic chimeric antigen receptors (CAR) targeting the HER2 molecule
Time Frame:6 weeks
Safety Issue:
Description:To evaluate the safety of autologous T cells expressing transgenic chimeric antigen receptors (CAR) targeting the HER2 molecule administered into the tumor, tumor resection cavity, and/or cerebrospinal fluid (CSF) space of subjects with progressive recurrent or refractory HER2-positive primary central nervous system (CNS) tumor or HER2 positive tumor metastatic to the CNS, excluding diffuse intrapontine glioma (DIPG), after standard of care interventions.

Secondary Outcome Measures

Measure:Number of Patients with a tumor response
Time Frame:6 weeks
Safety Issue:
Description:To evaluate the effects of gene modified T cells on measurable disease.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Baylor College of Medicine

Trial Keywords

  • CNS Tumors
  • T cells Expressing HER2-specific Chimeric Antigen Receptors
  • HER2-specific T cells
  • intracranial injection

Last Updated

July 21, 2019