Clinical Trials /

Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma

NCT00902044

Description:

Patients have a type of cancer called sarcoma. Because there is no standard treatment for the patients cancer at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from diseases caused by germs or toxic substances. They work by binding those germs or substances, which stops them from growing or exerting their toxic effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers: they both have shown promise, but have not been strong enough to cure most patients. We have found from previous research that we can put a new gene into T cells that will make them recognize cancer cells and kill them. We now want to see if we can put a new gene in these cells that will let the T cells recognize and kill sarcoma cells. The new gene that we will put in makes an antibody specific for HER2 (Human Epidermal Growth Factor Receptor 2) that binds to sarcoma cells. In addition it contains CD28, which stimulated T cells and make them last longer. In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in your body, and potentially kill cancer cells more effectively. We will use fludarabine or the combination of cyclophosphamide and fludarabine as the chemotherapy agents for lymphodepletion. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials. The purpose of this study is to find the largest safe dose of chimeric T cells, and to see whether this therapy might help patients with sarcoma. Another purpose is to see if it is safe to give HER2-CD28 T cells after lymphodepleting chemotherapy.

Related Conditions:
  • Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

URL:

https://clinicaltrials.gov/show/NCT00902044

Trial Eligibility

Document

Title

  • Brief Title: Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma
  • Official Title: Administration of Her2 Chimeric Antigen Receptor Expressing T Cells for Subjects With Advanced Sarcoma (HEROS)

Clinical Trial IDs

  • ORG STUDY ID: 24489-HEROS
  • SECONDARY ID: HEROS
  • NCT ID: NCT00902044

Conditions

  • Sarcoma

Interventions

DrugSynonymsArms
FludarabineFludaraCAR Positive cells
CyclophosphamideCytoxanCAR Positive cells

Purpose

Patients have a type of cancer called sarcoma. Because there is no standard treatment for the patients cancer at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from diseases caused by germs or toxic substances. They work by binding those germs or substances, which stops them from growing or exerting their toxic effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers: they both have shown promise, but have not been strong enough to cure most patients. We have found from previous research that we can put a new gene into T cells that will make them recognize cancer cells and kill them. We now want to see if we can put a new gene in these cells that will let the T cells recognize and kill sarcoma cells. The new gene that we will put in makes an antibody specific for HER2 (Human Epidermal Growth Factor Receptor 2) that binds to sarcoma cells. In addition it contains CD28, which stimulated T cells and make them last longer. In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in your body, and potentially kill cancer cells more effectively. We will use fludarabine or the combination of cyclophosphamide and fludarabine as the chemotherapy agents for lymphodepletion. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials. The purpose of this study is to find the largest safe dose of chimeric T cells, and to see whether this therapy might help patients with sarcoma. Another purpose is to see if it is safe to give HER2-CD28 T cells after lymphodepleting chemotherapy.

Detailed Description

      Because the cells have a new gene in them the patient will be followed for a total of 15
      years to see if there are any long term side effects of gene transfer.

      When the patient is enrolled on this study, they will be assigned a dose of HER2-CD28 T
      cells. Depending on which dose level they are assigned, they will receive one of the
      following:

      HER2-CD28 T cells and fludarabine (patient will receive fludarabine for 5 days followed by
      injection of HER2-CD28 T cells)

      OR

      HER2-CD28 T cells, fludarabine and cyclophosphamide (patient will receive fludarabine and
      cyclophosphamide for 2 days, fludarabine alone for an additional 3 days, and 2 days of rest
      before receiving the HER2-CD28 T cells.).

      The HER2-CD28 T cells will be given into the vein through an IV line. The injection will take
      between 1 and 10 minutes. The patient will be followed in the clinic after the injection for
      1 to 4 hours.

      Each patient will be followed for 6 weeks after the T-cell infusion for evaluation of
      toxicity. They will have standard tests and procedures as well as research blood draws.

      If the patient has stable disease (the tumor did not grow) or there is a reduction in the
      size of the tumor on imaging studies after the T-cell infusion, they can receive additional
      doses of the T cells at 6 to 12 weeks intervals. For the first two subsequent HER2-specific
      T-cell infusions, patients will be able to receive additional lymphodepleting chemotherapy
      according to their dose levels.

Trial Arms

NameTypeDescriptionInterventions
Autologous HER2-specific T cellsExperimentalTHIS ARM IS CLOSED Dose Level 1: 1x10^4 cells/m2 Dose Level 2: 3x10^4 cells/m2 Dose Level 3: 1x10^5 cells/m2 (NOT BEING USED) Dose Level 4: 3x10^5 cells/m2 (NOT BEING USED) Dose Level 5: 1x10^6 cells/m2 Dose Level 6: 3x10^6 cells/m2 Dose Level 7: 1x10^7 cells/m2 Dose Level 8: 3x10^7 cells/m2 Dose Level 9: 1x10^8 cells/m2
    HER2-specific T cells+fludarabineExperimentalAutologous HER2-specific T cells+fludarabine: Dose Level 9A: fludarabine followed by 1x10^8 cells/m^2
    • Fludarabine
    HER2-specific T cells+fludarab.+cycloph.ExperimentalAutologous HER2-specific T cells+fludarabine+cyclophosphamide: Dose Level 9B: fludarabine + cyclophosphamide followed by 1x10^8 cells/m^2
    • Fludarabine
    • Cyclophosphamide
    CAR Positive cellsExperimentalDose Level 9C: fludarabine + cyclophosphamide followed by 1x10^8 cells/m^2 CAR positive cells/m^2
    • Fludarabine
    • Cyclophosphamide

    Eligibility Criteria

            INCLUSION CRITERIA:

        Procurement Eligibility:

          1. Diagnosis of refractory HER2-positive sarcoma or metastatic HER2-positive
             osteosarcoma.

          2. Karnofsky/Lansky score of 50 or greater

          3. Informed consent explained to, understood by and signed by patient/guardian.
             Patient/guardian given copy of informed consent.

        Treatment Eligibility:

          1. Diagnosis of refractory HER2-positive sarcoma or metastatic HER2-positive sarcoma with
             disease progression after receiving at least one prior systemic therapy.

          2. Recovered from acute toxic effects of all prior cytotoxic chemotherapy at least 4
             weeks before entering this study. PD1/PDL1 inhibitors will be allowed to continue
             during treatment if medically indicated.

          3. Normal ECHO (Left ventricular ejection fraction (LVEF) has to be within normal,
             institutional limits)

          4. Life expectancy 6 weeks or greater

          5. Karnofsky/Lansky score of 50 or greater

          6. Bilirubin 3x or less, AST 3x or less, Serum creatinine 2x upper limit of normal or
             less, Hgb 7.0 g/dl or greater, WBC greater than 2,000/ul, ANC greater than 1,000/ul,
             platelets greater than 100,000/ul. Creatinine clearance is needed for patients with
             creatinine greater than 1.5 times upper limit of normal.

          7. Pulse oximetry of 90% or greater on room air

          8. Sexually active patients must be willing to utilize one of the more effective birth
             control methods for 6 months after the CTL infusion. Male partner should use a condom

          9. Available autologous transduced T lymphocytes with 15% or more expression of HER2 CAR
             as determined by flow-cytometry and killing of HER2-positive targets 20 % or greater
             in cytotoxicity assay.

         10. Chest radiograph for baseline evaluation of lungs

         11. Informed consent explained to, understood by and signed by patient/guardian.
             Patient/guardian given copy of informed consent

        EXCLUSION CRITERIA:

        At time of Procurement:

          1. Known HIV positivity

          2. Severe previous toxicity from cyclophosphamide or fludarabine

        At time of Treatment:

          1. Severe intercurrent infection

          2. Known HIV positivity

          3. Pregnant or lactating

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

          5. Severe previous toxicity from cyclophosphamide or fludarabine
    Maximum Eligible Age:N/A
    Minimum Eligible Age:N/A
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Number of patients with dose limiting toxicity after one injection of HER2-specific T cells
    Time Frame:6 weeks
    Safety Issue:
    Description:To determine the safety of one intravenous injection of autologous T cells expressing HER2-specific chimeric antigen receptor (CAR) in patients with advanced HER2-positive sarcoma. To determine the safety of one intravenous injection of 1x10^8/m^2 autologous T cells after lymphodepleting chemotherapy.

    Secondary Outcome Measures

    Measure:Frequency of HER2-specific T cells pre and post injection
    Time Frame:15 years
    Safety Issue:
    Description:To assess the in vivo expansion and persistence of infused T cells using immunoassays and transgene detection
    Measure:Change in tumor size from pre to post injection
    Time Frame:6 weeks
    Safety Issue:
    Description:To assess the anti-tumor effects of the infused HER2-specific T cells

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Active, not recruiting
    Lead Sponsor:Baylor College of Medicine

    Trial Keywords

    • Refractory Sarcoma
    • Metastatic Sarcoma
    • Sarcoma
    • HER2-positive
    • Gene Therapy
    • HER2-specific T cells

    Last Updated

    August 24, 2021