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Localized Radiation Therapy or Recombinant Interferon Beta and Avelumab With or Without Cellular Adoptive Immunotherapy in Treating Patients With Metastatic Merkel Cell Carcinoma

NCT02584829

Description:

This phase I/II trial studies the side effects and how well localized radiation therapy or recombinant interferon beta and avelumab with or without cellular adoptive immunotherapy works in treating patients with Merkel cell carcinoma that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Interferon beta is a substance that can improve the body's natural response and may interfere with the growth of tumor cells. Monoclonal antibodies, such as avelumab, may help T lymphocytes kill tumor cells. For cellular adoptive immunotherapy, specific white blood cells are collected from the patient's blood and treated in the laboratory to recognize Merkel cell carcinoma. Infusing these cells back into the patient may help the body build an effective immune response to kill Merkel cell carcinoma. Giving localized radiation therapy or recombinant interferon beta and avelumab with or without cellular adoptive immunotherapy may be a better treatment for Merkel cell carcinoma.

Related Conditions:
  • Merkel Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Localized Radiation Therapy or Recombinant Interferon Beta and <span class="go-doc-concept go-doc-intervention">Avelumab</span> With or Without Cellular Adoptive Immunotherapy in Treating Patients With Metastatic Merkel Cell <span class="go-doc-concept go-doc-disease">Carcinoma</span>

Title

  • Brief Title: Localized Radiation Therapy or Recombinant Interferon Beta and Avelumab With or Without Cellular Adoptive Immunotherapy in Treating Patients With Metastatic Merkel Cell Carcinoma
  • Official Title: Study to Evaluate Cellular Adoptive Immunotherapy Using Polyclonal Autologous CD8+ Antigen-Specific T Cells for Metastatic Merkel Cell Carcinoma in Combination With MHC Class I Up-Regulation and the Anti-PD-L1 Antibody Avelumab
  • Clinical Trial IDs

    NCT ID: NCT02584829

    ORG ID: 9245

    NCI ID: NCI-2014-02462

    Trial Conditions

    Merkel Cell Polyomavirus Infection

    Stage IV Merkel Cell Carcinoma

    Trial Interventions

    Drug Synonyms Arms
    Avelumab MSB0010718C Group 1 (avelumab and MHC class I up-regulation), Group 2 (avelumab, MHC class I up-regulation, T cells)

    Trial Purpose

    This phase I/II trial studies the side effects and how well localized radiation therapy or
    recombinant interferon beta and avelumab with or without cellular adoptive immunotherapy
    works in treating patients with Merkel cell carcinoma that has spread to other parts of the
    body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors.
    Interferon beta is a substance that can improve the body's natural response and may
    interfere with the growth of tumor cells. Monoclonal antibodies, such as avelumab, may help
    T lymphocytes kill tumor cells. For cellular adoptive immunotherapy, specific white blood
    cells are collected from the patient's blood and treated in the laboratory to recognize
    Merkel cell carcinoma. Infusing these cells back into the patient may help the body build an
    effective immune response to kill Merkel cell carcinoma. Giving localized radiation therapy
    or recombinant interferon beta and avelumab with or without cellular adoptive immunotherapy
    may be a better treatment for Merkel cell carcinoma.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. Assess and compare the safety and potential toxicities associated with treating patients
    with metastatic Merkel cell carcinoma (MCC) with either major histocompatibility complex
    (MHC) up regulation and programmed cell death 1 (PD1)-axis blockade (Group 1), or MHC
    up-regulation, PD1-axis blockade and adoptive transfer of Merkel cell polyoma virus (MCPyV)
    T antigen (TAg)-specific polyclonal autologous cluster of differentiation (CD)8+ T cells
    (Group 2).

    II. Assess and compare the antitumor efficacy associated with treating patients with
    metastatic MCC with either MHC up-regulation and PD1-axis blockade (Group 1), or MHC
    up-regulation, PD1-axis blockade and adoptive transfer of MCPyV TAg-specific polyclonal
    autologous CD8+ T cells (Group 2).

    SECONDARY OBJECTIVES:

    I. Examine the in vivo persistence and, where evaluable, migration to tumor sites of
    adoptively transferred polyclonal CD8+ T cells targeting the MCPyV TAg (Group 2).

    II. Examine the in vivo functional capacity of adoptively transferred polyclonal CD8+ T
    cells targeting the MCPyV Tag (Group 2).

    III. Examine and compare evidence of epitope spreading with either MHC up-regulation and
    adoptive transfer of MHC up-regulation and PD1-axis blockade (Group 1), or MHC up
    regulation, PD1-axis blockade and adoptive transfer of MCPyV TAg-specific polyclonal
    autologous CD8+ T cells (Group 2).

    OUTLINE: Patients who do not have a human leukocyte antigen (HLA) type for which T cells can
    be generated or for whom T cells cannot be generated for technical issues are assigned to
    Group 1. Patients who have an HLA type for which T cells can be generated are assigned to
    Group 2.

    GROUP 1: Patients receive avelumab intravenously (IV) every 2 weeks for 12 months. Within
    7-10 days after completion of 1-3 doses of avelumab, patients receive MHC class I
    up-regulation intervention comprising either localized radiation therapy or recombinant
    interferon beta via intra-tumor injection.

    GROUP 2: Patients receive avelumab IV every 2 weeks for 12 months. Patients also receive MHC
    class I up-regulation intervention as in Group 1 between 7-10 days after the first infusion
    of avelumab and 2-5 days before the first infusion of MCPyV TAg-specific polyclonal
    autologous CD8+ T cells. Patients receive two infusions of MCPyV TAg-specific polyclonal
    autologous CD8+ T cells IV over 60-120 minutes.

    In both groups, MHC class I up-regulation treatment with or without T cell infusions may
    repeat if indicated.

    After completion of study treatment, patients are followed up at 12 months and then
    periodically thereafter.

    Trial Arms

    Name Type Description Interventions
    Group 1 (avelumab and MHC class I up-regulation) Experimental Patients receive avelumab IV every 2 weeks for 12 months. Within 7-10 days after completion of 1-3 doses of avelumab, patients receive MHC class I up-regulation intervention comprising either localized radiation therapy or recombinant interferon beta via intra-tumor injection. Avelumab
    Group 2 (avelumab, MHC class I up-regulation, T cells) Experimental Patients receive avelumab IV every 2 weeks for 12 months. Patients also receive MHC class I up-regulation intervention as in Group 1 between 7-10 days after the first infusion of avelumab and 2-5 days before the first infusion of MCPyV TAg-specific polyclonal autologous CD8+ T cells. Patients receive two infusions of MCPyV TAg-specific polyclonal autologous CD8+ T cells IV over 60-120 minutes. Avelumab

    Eligibility Criteria

    Inclusion Criteria:

    - Signed written informed consent

    - Histopathology documentation of MCC concurrent with the diagnosis of metastatic
    disease

    - Evidence of MCPyV TAg tumor expression

    - Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 at trial entry

    - Patients must have at least one bi-dimensionally measurable lesion by palpation,
    clinical exam, or radiographic imaging (X-ray, computed tomography [CT] scan,
    positron emission tomography [PET] scan, magnetic resonance imaging [MRI], or
    ultrasound)

    - For patients designated to be treated on Group 2: cardiac ejection fraction >= 35%;
    for patients with significant risk factors for coronary artery disease (Framingham
    risk score > 15%), a cardiac stress test is recommended

    - At least 3 weeks must have passed since any of the following: systemic
    corticosteroids, immunotherapy (for example, T-cell infusions, immunomodulatory
    agents, interleukins, MCC vaccines, intravenous immunoglobulin, expanded polyclonal
    tumor infiltrating lymphocytes [TIL] or lymphokine-activated killer [LAK] therapy),
    pentoxifylline, other small molecule or chemotherapy cancer treatment, other
    investigational agents or other agents that target Merkel cell carcinoma

    Exclusion Criteria:

    - Known active infections or oral temperature > 38.2 Celsius (C) fewer than 72 hours
    prior to receiving study treatment or systemic infection requiring chronic
    maintenance or suppressive therapy

    - White blood cells (WBC) < 200/mcl

    - Hemoglobin (Hb) < 8 g/dL

    - Absolute neutrophil count (ANC) < 1000/mcl

    - Platelets < 50,000/mcl

    - New York Heart Association functional class III-IV heart failure, symptomatic
    pericardial effusion, stable or unstable angina, symptoms of coronary artery disease,
    congestive heart failure, clinically significant hypotension, or history of an
    ejection fraction of =< 30 % (echocardiogram or multi gated acquisition scan [MUGA])

    - Clinically significant pulmonary dysfunction, as determined by medical history and
    physical exam; patients so identified will undergo pulmonary functions testing and
    those with forced expiratory volume in 1 second (FEV1) < 2.0 L or diffusion capacity
    of the lung for carbon monoxide (DLco) (corrected [corr] for hemoglobin [Hgb]) < 50%
    will be excluded

    - Creatinine clearance < 30 ml/min which cannot be attributed to MCC metastasis

    - Total bilirubin > 1.5 x upper limit of normal (ULN)

    - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 x ULN; for
    patients with liver metastases: AST/ALT > 5 x ULN

    - Active autoimmune disease (e.g. systemic lupus erythematosus, vasculitis,
    infiltrating lung disease, inflammatory bowel disease) whose possible progression
    during treatment would be considered unacceptable by the investigators

    - Symptomatic and untreated central nervous system (CNS) metastasis; however, patients
    with 1 to 2 asymptomatic, less than 1 cm brain/CNS metastases without significant
    edema may be considered for treatment; if sub-centimeter CNS lesions are noted at
    study entry, then repeat imaging will be performed, if more than 4 weeks have elapsed
    from the last scan

    - Any condition or organ toxicity that is deemed by the principal investigator (PI) or
    the attending physician to place the patient at unacceptable risk for treatment on
    the protocol

    - Pregnant women, nursing mothers, men or women of reproductive ability who are
    unwilling to use effective contraception or abstinence; women of childbearing
    potential must have a negative pregnancy test within two weeks prior to entry

    - Clinically significant and ongoing immune suppression including, but not limited to,
    systemic immunosuppressive agents such as cyclosporine or corticosteroids, chronic
    lymphocytic leukemia (CLL), uncontrolled human immunodeficiency virus (HIV)
    infection, or solid organ transplantation

    - Patients may not be on any other treatments for their cancer aside from those
    included in the protocol; patients may not undergo another form of treatment
    concurrently with this study

    - Known severe hypersensitivity reactions to monoclonal antibodies (grade >= 3 National
    Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version
    [v] 4.0), any history of anaphylaxis, or uncontrolled asthma

    - Vaccination with live inactivated viral strains for the prevention of infectious
    diseases within 4 weeks of the start of the study treatment, inactivated influenza
    vaccines are permitted while on trial

    - Known alcohol or drug abuse

    - Legal incapacity or limited legal capacity

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Evidence of response, based on median time to new metastasis

    Incidence of adverse events, evaluated according to the current guidelines in NCI Common Toxicity Criteria version 4.0

    Secondary Outcome Measures

    Disease response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1

    Evidence of epitope spreading

    Functional capacity of transferred T cells (Group 2)

    MCC-specific survival

    Persistence of transferred T cells in blood and tumor (Group 2)

    Trial Keywords