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.
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
