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Gene-Modified T Cells, Vaccine Therapy, and Ipilimumab in Treating Patients With Locally Advanced or Metastatic Malignancies

NCT02070406

Description:

This pilot phase I trial studies the side effects of taking ipilimumab after gene-modified T cells and vaccine therapy when treating patients with advanced cancer that has spread to other areas of the body and has not responded to standard therapies. This trial also will determine the best dose of Ipilimumab to use in this combination treatment. T cells are a special type of white blood cell (immune cell) that have the ability to kill cancer cells. T cells are taken from the blood and modified in the laboratory to recognize a specific protein expressed on cancer cells, called NY-ESO-1. This may allow the T cells to target and kill cancer cells that express that protein. Dendritic cells are another type of blood cell that can teach other cells in the body to look for cancer cells and attack them. Giving a dendritic cell vaccine with the NY-ESO-1 protein may help dendritic cells teach the immune system to target cancer cells expressing that protein, and further help the T cells attack cancer. Ipilimumab is a monoclonal antibody, a type of drug manufactured in the laboratory that is similar to antibodies made in the human body that fight off infection. Ipilimumab blocks a protein that turns down the immune system, so blocking this protein may make the immune system more active. This may increase the ability of immune cells to kill cancer cells and improve the effectiveness of the T cell transplant. Giving gene-modified T-cells, a dendritic cell vaccine, and ipilimumab together may teach the immune system to recognize and kill cancer cells that have the NY-ESO-1 protein.

Related Conditions:
  • Cancer
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Gene-Modified T Cells, Vaccine Therapy, and <span class="go-doc-concept go-doc-intervention">Ipilimumab</span> in Treating Patients With Locally Advanced or Metastatic Malignancies

Title

  • Brief Title: Gene-Modified T Cells, Vaccine Therapy, and Ipilimumab in Treating Patients With Locally Advanced or Metastatic Malignancies
  • Official Title: NY-ESO-1 TCR Engineered Adoptive Cell Transfer Therapy With CTLA4 Blockade
  • Clinical Trial IDs

    NCT ID: NCT02070406

    ORG ID: 13-001624

    NCI ID: NCI-2014-00221

    Trial Conditions

    Unspecified Adult Solid Tumor, Protocol Specific

    Trial Interventions

    Drug Synonyms Arms
    cyclophosphamide CPM, CTX, Cytoxan, Endoxan, Endoxana Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)
    fludarabine phosphate 2-F-ara-AMP, Beneflur, Fludara Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

    Trial Purpose

    This pilot phase I trial studies the side effects of taking ipilimumab after gene-modified T
    cells and vaccine therapy when treating patients with advanced cancer that has spread to
    other areas of the body and has not responded to standard therapies. This trial also will
    determine the best dose of Ipilimumab to use in this combination treatment. T cells are a
    special type of white blood cell (immune cell) that have the ability to kill cancer cells. T
    cells are taken from the blood and modified in the laboratory to recognize a specific
    protein expressed on cancer cells, called NY-ESO-1. This may allow the T cells to target and
    kill cancer cells that express that protein. Dendritic cells are another type of blood cell
    that can teach other cells in the body to look for cancer cells and attack them. Giving a
    dendritic cell vaccine with the NY-ESO-1 protein may help dendritic cells teach the immune
    system to target cancer cells expressing that protein, and further help the T cells attack
    cancer. Ipilimumab is a monoclonal antibody, a type of drug manufactured in the laboratory
    that is similar to antibodies made in the human body that fight off infection. Ipilimumab
    blocks a protein that turns down the immune system, so blocking this protein may make the
    immune system more active. This may increase the ability of immune cells to kill cancer
    cells and improve the effectiveness of the T cell transplant. Giving gene-modified T-cells,
    a dendritic cell vaccine, and ipilimumab together may teach the immune system to recognize
    and kill cancer cells that have the NY-ESO-1 protein.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. The safety of NY-ESO-1 T-cell receptor (TCR) transgenic adoptive cell transfer (ACT) has
    been reported. The current protocol includes the addition of the cytotoxic
    T-lymphocyte-associated protein 4 (CTLA4) blocking monoclonal antibody ipilimumab to NY ESO
    TCR ACT in a dose escalation scheme in two study cohorts at 1 and 3 mg/kg of ipilimumab
    intravenous (i.v.) every three weeks with a maximum of 4 doses (q3wx4).

    SECONDARY OBJECTIVES:

    I. To determine the feasibility of delivering the TCR transgenic cell dose and CTLA blockade
    to patients.

    II. To determine the persistence of NY-ESO-1 TCR-engineered peripheral blood mononuclear
    cells (PBMC) in serial peripheral blood samples and in biopsies of accessible metastatic
    lesions.

    III. To explore the use of positron emission tomography (PET)-based imaging using the PET
    tracer [18F] fluorodeoxy-glucose ([18F]FDG) with the goal of determining if the adoptively
    transferred NY-ESO-1 TCR-engineered PBMC when administered with ipilimumab home and expand
    in secondary lymphoid organs and tumor deposits.

    IV. Clinical antitumor activity recording objective response rate will be an exploratory
    endpoint in this pilot clinical trial.

    OUTLINE: This is a dose-escalation study of ipilimumab.

    CONDITIONING CHEMOTHERAPY REGIMEN: Patients receive cyclophosphamide IV on days -5 and -4
    and fludarabine phosphate IV over 30 minutes daily on days -4 to -1.

    NY-ESO-1 TCR PBMC INFUSION: Patients receive NY-ESO-1 reactive TCR retroviral vector
    transduced autologous T cells IV on day 0.

    IPILIMUMAB ADMINISTRATION: Patients receive ipilimumab IV over 90 minutes before the
    NY-ESO-1 TCR PBMC infusion on day 0 or after the infusion on day 1. Treatment repeats every
    3 weeks for up to 4 doses in the absence of disease progression or unacceptable toxicity.

    NY-ESO-1(157-165) PEPTIDE PULSED DENDRITIC CELL (DC) ADMINISTRATION: Patients receive
    NY-ESO-1(157-165) peptide pulsed DC vaccine intradermally (ID) on days 1, 14, and 30.

    LOW DOSE INTERLEUKIN-2 (IL-2) ADMINISTRATION: Patients receive aldesleukin (IL-2)
    subcutaneously (SC) twice daily (BID) on days 1-14.

    After completion of study treatment, patients are followed up periodically for 90 days,
    every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

    Trial Arms

    Name Type Description Interventions
    Treatment (gene-modified T-cells, vaccine therapy, ipilimumab) Experimental CONDITIONING CHEMOTHERAPY REGIMEN: Patients receive cyclophosphamide IV on days -5 and -4 and fludarabine phosphate IV over 30 minutes daily on days -4 to -1. NY-ESO-1 TCR PBMC INFUSION: Patients receive NY-ESO-1 reactive TCR retroviral vector transduced autologous T cells IV on day 0. IPILIMUMAB ADMINISTRATION: Patients receive ipilimumab IV over 90 minutes before the NY-ESO-1 TCR PBMC infusion on day 0 or after the infusion on day 1. Treatment repeats every 3 weeks for up to 4 doses in the absence of disease progression or unacceptable toxicity. NY-ESO-1(157-165) PEPTIDE PULSED DC ADMINISTRATION: Patients receive NY-ESO-1(157-165) peptide pulsed DC vaccine ID on days 1, 14, and 30. LOW DOSE IL-2 ADMINISTRATION: Patients receive aldesleukin (IL-2) SC BID on days 1-14. cyclophosphamide, fludarabine phosphate

    Eligibility Criteria

    Inclusion Criteria:

    - Stage IV or locally advanced cancers for which no alternative therapies with proven
    survival advantage are available

    - At least 1 lesion amenable for outpatient biopsies; this should be a cutaneous or
    palpable metastatic site or a deeper site accessible by image-guided biopsy that is
    deemed safe to access by the treating physicians and interventional radiologists;
    patients without accessible lesions for biopsy but with prior tissue available from
    metastatic disease would be eligible at the investigator's discretion

    - NY-ESO-1 positive malignancy by immunohistochemistry (IHC) utilizing commonly
    available NY-ESO-1 antibodies

    - Human leukocyte antigen (HLA)-A*0201 (HLA-A2.1) positivity by molecular subtyping

    - Life expectancy greater than 3 months assessed by a study physician

    - A minimum of one measurable lesion defined as:

    - Meeting the criteria for measurable disease according to Response Evaluation
    Criteria in Solid Tumors (RECIST)

    - Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be
    accurately measured and recorded by color photography with a ruler to document
    the size of the target lesion(s)

    - No restriction based on prior treatments

    - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

    - Absolute neutrophil count >= 1.5 x 10^9 cells/L

    - Platelets >= 100 x 10^9/L

    - Hemoglobin >= 10 g/dL

    - Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x upper limit of normal
    (ULN) (=< 5 x ULN, if documented liver metastases are present)

    - Total bilirubin =< 2 x ULN (except patients with documented Gilbert's syndrome)

    - Creatinine < 2 mg/dl (or a glomerular filtration rate > 60)

    - Must be willing and able to accept two leukapheresis procedures

    - Must be willing and able to provide written informed consent

    Exclusion Criteria:

    - Previously known hypersensitivity to any of the agents used in this study

    - Received systemic treatment for cancer, including immunotherapy, within one month
    prior to initiation of dosing within this protocol

    - History of, or significant evidence of risk for, chronic inflammatory or autoimmune
    disease (eg, Addison's disease, multiple sclerosis, Graves' disease, Hashimoto's
    thyroiditis, inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic
    lupus erythematosus, hypophysitis, pituitary disorders, etc.); patients will be
    eligible if prior autoimmune disease is not deemed to be active (e.x. fibrotic damage
    of the thyroid after thyroiditis or its treatment, with stable thyroid hormone
    replacement therapy); vitiligo will not be a basis for exclusion

    - History of inflammatory bowel disease, celiac disease, or other chronic
    gastrointestinal conditions associated with diarrhea or bleeding, or current acute
    colitis of any origin

    - Potential requirement for systemic corticosteroids or concurrent immunosuppressive
    drugs based on prior history or received systemic steroids within the last 4 weeks
    prior to enrollment (inhaled or topical steroids at standard doses are allowed)

    - Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired
    immune deficiency state, which would increase the risk of opportunistic infections
    and other complications during chemotherapy-induced lymphodepletion; if there is a
    positive result in the infectious disease testing that was not previously known, the
    patient will be referred to their primary physician and/or infectious disease
    specialist

    - Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would
    increase the likelihood of hepatic toxicities from the chemotherapy conditioning
    regimen and supportive treatments; if there is a positive result in the infectious
    disease testing that was not previously known, the patient will be referred to their
    primary physician and/or infectious disease specialist

    - Dementia or significantly altered mental status that would prohibit the understanding
    or rendering of informed consent and compliance with the requirements of this
    protocol

    - Clinically active brain metastases; radiological documentation of absence of active
    brain metastases at screening is required for all patients; prior evidence of brain
    metastasis successfully treated with surgery or radiation therapy will not be
    exclusion for participation as long as they are deemed under control at the time of
    study enrollment

    - Pregnancy or breast-feeding; female patients must be surgically sterile or be
    postmenopausal for two years, or must agree to use effective contraception during the
    period of treatment and 6 months after; all female patients with reproductive
    potential must have a negative pregnancy test (serum/urine) within 14 days from
    starting the conditioning chemotherapy; the definition of effective contraception
    will be based on the judgment of the study investigators

    - Since IL-2 is administered following cell infusion:

    - Patients will be excluded if they have a history of clinically significant
    electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia or
    arrhythmias and have a left ventricular ejection fraction (LVEF) < 45% on a
    cardiac stress test (stress thallium, stress multi gated acquisition (MUGA)
    scan, dobutamine echocardiogram, or other stress test)

    - Similarly, patients who are 50 years old with a baseline LVEF < 45% will be
    excluded

    - Patients with ECG results of any conduction delays (PR interval > 200 ms,
    corrected QT interval [QTC] > 480 ms), sinus bradycardia (resting heart rate <
    50 beats per minute), sinus tachycardia (heart rate > 120 beats per minute) will
    be evaluated by a cardiologist prior to starting the trial; patients with any
    arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy
    (defined as > 20 PVCs per minute), ventricular tachycardia, 3rd degree heart
    block will be excluded from the study unless cleared by a cardiologist

    - Patients with pulmonary function test abnormalities as evidenced by a forced
    expiratory volume of the lung in 1 second (FEV1)/forced vital capacity (FVC) <
    70% of predicted for normality will be excluded

    - Evidence of diverticulitis at baseline, including evidence limited to computed
    tomography (CT) scan only

    Minimum Eligible Age: 16 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of toxicity as defined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0

    Maximum tolerable dose (MTD) based on the number of subjects experiencing dose limiting toxicities (DLTs)

    Secondary Outcome Measures

    Feasibility of NY-ESO-1 TCR cells, determined by incidence of preparation not meeting the lot release criteria

    Transgenic cell persistence, analyzed using immune monitoring and molecular techniques

    NY-ESO-1 TCR transgenic cell tumor trafficking (imaging), assessed using 18F-FDG PET

    Antitumor activity, assessed using RECIST

    Trial Keywords