Clinical Trials /

Gene and Vaccine Therapy in Treating Patients With Advanced Malignancies

NCT01697527

Description:

This phase II trial will examine whether genetically reprogramming a patient's disease fighting white blood cells may build an immune response to kill cancer cells that express the NY-ESO-1 protein. In this study, this genetic therapy will be given during a stem cell transplant along with a vaccine therapy. The vaccine will be made using the NY-ESO-1 protein and may help to stimulate the engineered immune response to tumor cells.

Related Conditions:
  • Cancer
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Gene and Vaccine Therapy in Treating Patients With Advanced Malignancies

Title

  • Brief Title: Gene and Vaccine Therapy in Treating Patients With Advanced Malignancies
  • Official Title: Adoptive Transfer of NY-ESO-1 TCR Engineered Peripheral Blood Mononuclear Cells (PBMC) After a Nonmyeloablative Conditioning Regimen, With Administration of NY-ESO-1157-165 Pulsed Dendritic Cells and Interleukin-2, in Patients With Advanced Malignancies
  • Clinical Trial IDs

    NCT ID: NCT01697527

    ORG ID: 12-000153

    NCI ID: NCI-2012-01548

    Trial Conditions

    Malignant Neoplasm

    Trial Interventions

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

    Trial Purpose

    This phase II trial will examine whether genetically reprogramming a patient's disease
    fighting white blood cells may build an immune response to kill cancer cells that express
    the NY-ESO-1 protein. In this study, this genetic therapy will be given during a stem cell
    transplant along with a vaccine therapy. The vaccine will be made using the NY-ESO-1 protein
    and may help to stimulate the engineered immune response to tumor cells.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate whether we can safely administer NY-ESO-1 T cell receptor transduced
    autologous peripheral blood mononuclear cells (PBMCs) (up to 1x10^9 cells) along with an
    NY-ESO-1 dendritic cell vaccine and low dose IL-2 to patients with advanced malignancies.

    II. To evaluate the feasibility of delivering two patient-specific cell therapies, the
    NY-ESO-1 TCR transgenic peripheral blood mononuclear cell (PBMC) and NY-ESO-1 (157-165)
    peptide pulsed dendritic cells (DC), within a technically challenging study design that
    requires other significant interventions, like a lymphodepleting conditioning regimen and
    post-infusion of subcutaneous low dose interleukin (IL)-2 (aldesleukin).

    III. To determine the rate of objective tumor responses, by Response Evaluation Criteria in
    Solid Tumors (RECIST) objective response criteria.

    SECONDARY OBJECTIVES:

    I. To determine the persistence of NY-ESO-1 TCR-engineered cells. This will be determined by
    temporally analyzing peripheral blood samples for the presence of T cells with the
    transduced NY-ESO-1 TCR by tetramer or dextramer analysis.

    II. To explore the homing and persistence of the adoptively transferred NY-ESO-1
    TCR-engineered PBMC in secondary lymphoid organs and tumor deposits via positron emission
    tomography (PET)-based imaging using the PET tracer fluorodeoxyglucose ([18F]FDG).

    OUTLINE:

    CONDITIONING: Patients receive cyclophosphamide intravenously (IV) over 1 hour on days -5 to
    -4 and fludarabine phosphate IV over 30 minutes on days -4 to -1.

    TRANSPLANT: Patients receive NY-ESO-1 TCR transduced autologous PBMC IV on day 0. Patients
    also receive NY-ESO-1 (157-165) peptide pulsed dendritic cell vaccine therapy intradermally
    (ID) on days 1, 14, and 30 and aldesleukin subcutaneously (SC) twice daily (BID) on days
    1-14. Patients may receive 3 additional doses of NY-ESO-1 (157-165) peptide pulsed dendritic
    cell vaccine therapy after day 90.

    After completion of study treatment, patients are followed up at 30, 45, 60, and 75 days;
    every 3 months for 2 years; every 6 months for 3 years; and annually thereafter.

    Trial Arms

    Name Type Description Interventions
    Treatment (gene and vaccine therapy) Experimental CONDITIONING: Patients receive cyclophosphamide IV over 1 hour on days -5 to -4 and fludarabine phosphate IV over 30 minutes on days -4 to -1. TRANSPLANT: Patients receive NY-ESO-1 reactive TCR retroviral vector transduced autologous PBL IV on day 0. Patients also receive NY-ESO-1 (157-165) peptide pulsed dendritic cell vaccine therapy ID on days 1, 14, and 30 and aldesleukin SC BID on days 1-14. Patients may receive 3 additional doses of NY-ESO-1 (157-165) peptide pulsed dendritic cell vaccine therapy after day 90. fludarabine phosphate, cyclophosphamide

    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 an outpatient biopsy; 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 IHC utilizing commonly available NY-ESO-1 antibodies.

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

    - Age greater than or equal to 16 years old.

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

    - A minimum of one measurable lesion defined as:

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

    - For patients with skin metastases, lesions 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.

    - ECOG performance status (PS) 0 or 1.

    - Adequate bone marrow and hepatic function determined within 30-60 days prior to
    enrollment, defined as:

    1. Absolute neutrophil count > or = 1.5 x 109 cells/L.

    2. Platelets > or = 100 x 109/L.

    3. Hemoglobin > or = 10 g/dL.

    4. Aspartate and alanine aminotransferases (AST, ALT) < or = 2.5 x ULN (< or = 5 x
    ULN, if documented liver metastases are present).

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

    6. Creatinine < 2 mg/dl (or a glomerular filtration rate > 60 mL/min).

    - Must be willing and able to accept at least two leukapheresis procedures.

    - Must be willing and able to accept at least two tumor biopsies.

    - 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. However, cell harvesting by
    leukapheresis may be performed before one month from prior therapy if the study
    investigators consider that it will not have a detrimental impact on the generation
    of the two cell therapies in 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).

    - HIV seropositivity or other congenital or acquired immune deficiency state, which
    would increase the risk of opportunistic infections and other complications during
    chemotherapy-induced lympho-depletion. 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:

    1. Patients will be excluded if they have a history of clinically significant 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 MUGA, dobutamine echocardiogram, or other stress test)

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

    3. Patients with ECG results of any conduction delays (PR interval >200ms, QTC >
    480ms), sinus bradycardia (resting heart rate <50 beats per minute), sinus
    tachycardia (HR>120 beats per minute) will be evaluated by a cardiologist prior
    to starting the trial. Patients with any arrhythmias, including atrial
    fibrillation/atrila 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.

    4. Patients with pulmonary function test abnormalities as evidenced by a FEV1/FVC<
    70% of predicted for normality will be excluded.

    - Received 3 or more prior myelotoxic treatment regimens.

    Minimum Eligible Age: 16 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Clinical response

    Secondary Outcome Measures

    NY-ESO-1 TCR transgenic cell persistence, quantitated in PBMC samples

    NY-ESO-1 TCR transgenic cell tumor trafficking

    Trial Keywords