This phase I/II trial studies the side effects of gene-modified immune cells (FH-MCVA2TCR)
and to see how well they work in treating patients with Merkel cell cancer that has spread to
other parts of the body (metastatic) or that cannot be removed by surgery (unresectable).
Placing a gene that has been created in the laboratory into immune cells may improve the
body's ability to fight Merkel cell cancer.
OUTLINE: This is a dose escalation study of FH-MCVA2TCR autologous T-cells.
Approximated 5 days prior to receiving FH-MCVA2TCR T-cells, patients undergo radiation
therapy for 1 fraction per standard of care. Patients receive FH-MCVA2TCR T-cells
intravenously (IV) over 60-120 minutes. Beginning 14 days after receiving FH-MCVA2TCR
T-cells, patients also receive standard of care avelumab IV over 1 hour every 2 weeks for 1
year or pembrolizumab IV over 30 minutes every 3 weeks for 1 year in the absence of disease
progression or unacceptable toxicity. Patients with partial response or stable disease may
then receive an additional cycle of FH-MCVA2TCR T-cells.
After completion of study treatment, patients are followed up periodically for up to 15
years.
Inclusion Criteria:
- EVALUATION: Metastatic or unresectable Merkel cell polyomavirus (MCPyV)-associated
Merkel cell carcinoma (VP-MCC) that has progressed on or after prior treatment with a
PD-1 axis immune checkpoint inhibitor.
- EVALUATION: Individuals that may be consented to undergo evaluation to determine
potential eligibility must have a history of metastatic or unresectable Merkel cell
carcinoma (MCC) (as documented by medical record).
- EVALUATION: Be capable of understanding and providing informed consent.
- Participants must have metastatic or unresectable, histologically confirmed
virus-positive MCC. Confirmation of diagnosis must be or have been performed by
internal pathology review of initial or subsequent biopsy or other pathologic material
at Fred Hutch/Seattle Cancer Care Alliance (SCCA).
- Approximately 80% of MCCs are caused by Merkel cell polyomavirus (MCPyV) T Antigens
and the treatment is expected to only be effective in this population. Merkel cell
polyomavirus positivity may be established through one of two means: positive Merkel
cell polyomavirus T antigen serology (preferred) or immunohistochemistry of a primary
or metastatic MCC tumor lesion (if T antigen seronegative).
- MCPyV T Antigen serology will be performed with the anti-Merkel cell panel (AMERK)
assay run through the University of Washington Medical Center Laboratory Medicine
Clinical Immunology Laboratory. Positivity will be defined as a Merkel oncoprotein
antibody titer (MSCTT) of >= 75 standard titer units (STU) at any time point from
initial diagnosis onward. Patients with negative T antigen serology but MCPyV positive
tumor by other methodologies will be considered for additional MCPyV testing as
clinically appropriate, as the T antigen serology assays are highly specific but
incompletely sensitive for MCPyV status. In this case, immunohistochemistry of any
tumor lesion will be performed with the CM2B4 Merkel cell polyomavirus T antigen
antibody. Expression of MCPyV in at least 10% of tumor cells will be considered
positive. CM2B4 staining performed at any point clinically and at any clinical
laboratory may be accepted. However, if CM2B4 staining has not been previously
performed by a clinical pathology laboratory as part of MCC diagnostic workup, it will
be performed in a clinical diagnostic pathology laboratory at University of Washington
(UW)/Fred Hutchinson Cancer Research Center (FHCRC)/SCCA as per standard staining
protocols. Persons are not required to have both CM2B4 positivity and seropositivity;
either will be acceptable confirmation of viral status and if one negative and the
other positive the patient will remain eligible provided other criteria are met.
- Patients must have been previously treated with at least one dose of a PD-1 axis
inhibitor (e.g. PD-1 or PD-L1 inhibiting monoclonal antibody such as pembrolizumab,
nivolumab, avelumab, atezolizumab, durvalumab), developed progression of their MCC
tumor on or after treatment, and not developed grade 3 or higher toxicity. At least
four weeks must have passed between the administration of the first dose of PD-1 axis
inhibitor and determination of progression. If there is significant clinical concern
for pseudoprogression (i.e. progression developed rapidly after checkpoint inhibitor
therapy), biopsy must be performed to demonstrate true progression. Patients may have
received 1 or more prior systemic regimens for MCC. There is no upper limit on prior
regimens. Patients may have received prior anti-PD-1/anti-PD-L1 in the neoadjuvant or
adjuvant setting.
- Participants must be HLA-A*02:01 in order for infused transgenic T cells to recognize
antigen-MHC complexes. HLA typing for HLA-A2 should be determined through molecular
approaches at a clinical laboratory licensed for HLA testing.
- Life expectancy must be anticipated to be > 3 months at trial entry.
- Fewer than 0.5% of MCC occur in individuals aged 30 years or younger, thus the
protocol includes only adult patients.
- Capable of understanding and providing a written informed consent.
- If fertile, willingness to comply with reproductive requirements.
- Karnofsky performance status of >= 60%.
- Should there be no tumor tissue that is accessible for biopsy, patients will still be
considered for participation, at discretion of the investigator. Similarly, should an
investigator determine that a biopsy cannot be performed safely for clinical reasons
biopsies may be cancelled or retimed.
- At least 3 weeks must have passed since any: immunotherapy (for example, T-cell
infusions, immunomodulatory agents, interleukins, MCC vaccines, intravenous
immunoglobulin, expanded polyclonal tumor infiltrating lymphocyte [TIL] or
lymphokine-activated killer cell [LAK] therapy), natural killer (NK) therapy, small
molecule or chemotherapy cancer treatment, other investigational agents or other
systemic agents that target MCC. There is no washout period for radiation.
- Serum creatinine < 2.5 or estimated glomerular filtration rate (eGFR) > 30.
- Total bilirubin (tBili) < 3.0. Patients with suspected Gilbert syndrome may be
included if Tbili > 3 but no other evidence of hepatic dysfunction.
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x upper limit
of normal (ULN).
- =< grade 1 dyspnea.
- Oxygen saturation (SaO2) >= 92% on ambient air.
- If pulmonary function tests (PFTs) are performed based on the clinical judgment of the
treating physician, patients with forced expiratory volume in one second (FEV1) >= 50%
of predicted and diffusion capacity of the lung for carbon monoxide (DLCO) (corrected)
of >= 40% of predicted will be eligible.
- Patients 60 years of age or older are required to have left ventricular ejection
fraction (LVEF) evaluation performed within 1 year prior to study treatment. LVEF may
be established with echocardiogram or multigated acquisition (MUGA) scan, and must be
>= 35%. Cardiac evaluation for other patients is at the discretion of the treating
physician.
- Absolute neutrophil count (ANC) > 1000 cells/mm^3.
- Absolute lymphocyte count (ALC) > 200 cells/mm^3.
- Hematocrit (HCT) > 30%.
- Platelet count > 50K.
Exclusion Criteria:
- Active autoimmune disease requiring immunosuppressive therapy is excluded unless
discussed with the principal investigator (PI).
- Kidney transplant will be considered on a case by case basis requiring discussion with
PI. If kidney transplant, patient must have dialysis access, dialysis plan, supportive
nephrologist, willingness to stop transplant immunosuppression, and express
understanding that rejection is likely. Dialysis or costs related to transplant kidney
will not be supported by the study. Participants having had any other solid organ
transplants will be excluded, as will those with a history of allogeneic stem cell
transplant.
- Corticosteroid therapy at a dose equivalent of > 10 mg prednisone per day.
- Concurrent use of other investigational agents or MCC directed therapies.
- Any medical or psychological condition other than Merkel cell carcinoma that would
significantly increase the risk of harm to a subject or interfere with the
interpretation of trial endpoints.
- Active uncontrolled infection. Human immunodeficiency virus (HIV) positive
participants on highly active antiretroviral therapy (HAART) with a CD4 count > 500
cells/mm^3 are considered controlled, as are individuals with a history of hepatitis C
who have successfully completed antiviral therapy with an undetectable viral load, and
those with hepatitis B who have hepatitis well controlled on medication.
- Uncontrolled concurrent illness. Participants may not have uncontrolled or concurrent
illness including, but not limited to, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.
- Untreated brain metastases. Participants with small asymptomatic brain metastases (< 1
cm) or those with brain metastases previously treated with surgery or radiotherapy
will be considered for inclusion at discretion of principal investigator, so long as
other eligibility criteria are met.
- Grade 3 or higher immune related adverse event (iRAE) to any prior PD-1 axis blocking
agent. iRAEs are persistent T cell mediated inflammatory syndromes caused by PD-1 or
PD-L1 inhibitors including colitis, nephritis, pneumonitis, myositis, hepatitis,
encephalitis.
- Participants receiving treatment for prior immune-related adverse event (iRAE) are
excluded, with exception of hormone supplementation or corticosteroid therapy at
equivalent of up to 10 mg prednisone per day, unless otherwise approved by PI.
- Study participants must not have significant active underlying neurologic disease,
unless approved by PI. Mild neuropathy related to diabetes or prior chemotherapy is
acceptable.
- Other medical, social, or psychiatric factor that interferes with medical
appropriateness and/or ability to comply with study, as determined by PI.
