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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

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ClinicalTrials.gov Identifier: NCT02584829
Recruitment Status : Active, not recruiting
First Posted : October 23, 2015
Last Update Posted : November 20, 2018
Sponsor:
Collaborators:
EMD Serono
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Merkel Cell Polyomavirus Infection Stage IV Merkel Cell Carcinoma AJCC v7 Drug: Avelumab Other: Laboratory Biomarker Analysis Biological: MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells Radiation: Radiation Therapy Biological: Recombinant Interferon Beta Phase 1 Phase 2

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 are assigned to 1 of 2 groups.

GROUP 1: 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 receive avelumab intravenously (IV) over 1 hour 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 who have an HLA type for which T cells can be generated receive avelumab IV over 1 hour 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 6, 2015
Estimated Primary Completion Date : June 20, 2022


Arm Intervention/treatment
Experimental: Group 1 (avelumab and MHC class I up-regulation)
Patients who do not have a HLA type for which T cells can be generated or for whom T cells cannot be generated for technical issues receive avelumab intravenously (IV) over 1 hour 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.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Other: Laboratory Biomarker Analysis
Correlative studies

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation

Biological: Recombinant Interferon Beta
Given via intra-tumor injection
Other Names:
  • Beta Interferon
  • Betantrone
  • Feron
  • Human Interferon Beta
  • Interferon Beta
  • Interferon, Beta
  • Interferon-B
  • Interferon-beta
  • Naferon

Experimental: Group 2 (avelumab, MHC class I up-regulation, T cells)
Patients who have an HLA type for which T cells can be generated receive avelumab IV over 1 hour 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.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells
Given IV

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation

Biological: Recombinant Interferon Beta
Given via intra-tumor injection
Other Names:
  • Beta Interferon
  • Betantrone
  • Feron
  • Human Interferon Beta
  • Interferon Beta
  • Interferon, Beta
  • Interferon-B
  • Interferon-beta
  • Naferon




Primary Outcome Measures :
  1. Evidence of response, based on median time to new metastasis [ Time Frame: Up to 4 years ]
    Will be observed.

  2. Incidence of adverse events, evaluated according to the current guidelines in National Cancer Institute (NCI) Common Toxicity Criteria version 4.0 [ Time Frame: Up to 12 months after the last infusion ]
    Evidence and nature of toxicity related to the treatment will be assessed and compared between groups.


Secondary Outcome Measures :
  1. Disease response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 [ Time Frame: Up to 4 years ]
    Will be observed.

  2. Evidence of epitope spreading [ Time Frame: Up to 4 years ]
    Quantification of the overall recognition of the MCPyV T-antigen for each patient will likely be performed by testing the reactivity of whole peripheral blood mononuclear cells (PBMC) before and at indicated timepoints after treatment to peptides 15 amino acids (aa) in length offset by 5 aa bases spanning the whole T-antigen protein to include both CD8 and CD4 responses regardless of the HLA type of the patient. The reactivity will be detected using IFN gamma secretion in a human IFN gamma enzyme-linked immunospot assay. Results will be presented as the number of spot forming cells/10^5 PBMCs.

  3. Functional capacity of transferred T cells (Group 2) [ Time Frame: Up to 4 years ]
    To evaluate the direct ex vivo function of the transferred cells, where possible, tetramer+ cells within collected peripheral blood mononuclear cells (PBMCs) will be evaluated for production of intracellular cytokines including interferon (IFN), tumor necrosis factor alpha and interleukin-2 in response to cognate antigen using an intracellular cytokine assay.

  4. Merkel cell carcinoma (MCC)-specific survival [ Time Frame: Up to 4 years ]
    Will be observed.

  5. Persistence of transferred T cells in blood and tumor (Group 2) [ Time Frame: Up to 4 years ]
    Will be observed.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed written informed consent
  • Confirmation of MCC by internal pathology review of initial or subsequent biopsy or other pathologic material
  • If an accessible lesion is present, a biopsy will be performed within 6 weeks of the start of study intervention; the results of the biopsy must be obtained prior to initiation of study intervention
  • Evidence of MCPyV TAg tumor expression by immunohistochemistry on any prior or current tumor specimen or viral oncoprotein antibody confirmation within 6 weeks of the start of study intervention
  • 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 within 6 weeks of the start of study intervention (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 systemic 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 2-6 weeks prior to treatment
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02584829


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
EMD Serono
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Aude Chapuis Fred Hutch/University of Washington Cancer Consortium

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Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT02584829     History of Changes
Other Study ID Numbers: 9245
NCI-2014-02462 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
FHCRC 9245
9245 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
K24CA139052 ( U.S. NIH Grant/Contract )
P30CA015704 ( U.S. NIH Grant/Contract )
R01CA176841 ( U.S. NIH Grant/Contract )
First Posted: October 23, 2015    Key Record Dates
Last Update Posted: November 20, 2018
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma, Merkel Cell
Polyomavirus Infections
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Interferons
Interferon-beta
Antibodies, Monoclonal
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs