Pembrolizumab or Avelumab and Cryoablation for the Treatment of Patients with Metastatic Urothelial Cancer

Inclusion Criteria

• Patients who will receive pembrolizumab during the study are either not eligible for any platinum-containing chemotherapy, or have had disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
• Patients who will receive avelumab during the study are either receiving it as maintenance treatment (no disease progression following first-line platinum-containing chemotherapy) or are receiving it after disease progression during or following platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
• The subject has read, signed and dated the informed consent form (ICF), having been advised of the risks and benefits of the trial in a language understood by the subject
• Age >= 18 years at date of ICF signature having the ability to comply with the protocol
• Proof of medical insurance coverage
• Histologically or cytologically documented metastatic (M1, Stage IV) urothelial carcinoma (including renal pelvis, ureters, urinary bladder, urethra)
• Measurable metastatic disease. Subject must have at least one site of metastatic disease ≥ 1 cm in size (in any dimension; can be measurable or non-measurable per RECIST v1.1) and amenable to percutaneous image-guided cryoablation based on routine Interventional Radiology criteria. Metastasis sites amenable to cryoablation to include lymph node, peritoneum, liver, soft tissue, adrenal glands, kidney, lung, and bone. Must additionally have measurable disease (by RECIST v1.1) independent of the lesion to be ablated (i.e., patient must have more than one metastasis)
• Life expectancy >= 12 weeks
• Performance score (PS) Eastern Cooperative Oncology Group (ECOG) 0 or 1
• Absolute neutrophil count (ANC) > 1 x 10^9/L
• Platelets > 75 x 10^9/L
• Alanine aminotransferase / aspartate aminotransferase (ALT / AST) < 5 x upper limit of normal (ULN)
• Total bilirubin < 3 mg/dL
• International normalized ratio (INR) < 1.7
• Creatinine clearance (CrCl) > 30 ml/min

Exclusion Criteria

• Lesion to undergo cryoablation cannot have had prior radiation therapy or other locoregional therapy
• Inability to lie flat for the cryoablation procedure
• Known significant immunodeficiency due to underlying illness (e.g. human immunodeficiency virus [HIV] / acquired immunodeficiency syndrome [AIDS]) and/or blood CD4+ T cells < 200/ul
• History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, granulomatosis with polyangiitis, Sjogren’s syndrome, Guillain- Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
• Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this trial
• Patients with controlled type I diabetes mellitus on a stable dose of insulin regimen are eligible for this trial
• Patients with history of vitiligo and controlled psoriasis are eligible for the trial
• Continued adverse events from a previously administered chemotherapeutic agents. Grade 1 adverse events and ongoing toxicities such as alopecia are exempt
• Treatment with systemic corticosteroids exceeding the equivalent of 10 mg/day of prednisone or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, and anti−tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
• Patients who receive acute, low-dose, systemic corticosteroid medications (e.g., a onetime dose of dexamethasone for nausea) or for prevention of hypersensitivity reactions to contrast agents may be enrolled in the trial
• Anticoagulant or anti-platelet medication that cannot be interrupted prior to cryoablation
• Pregnant or lactating
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicated the use of an investigational drug or that could affect the interpretation of the results or render the patient at high risk from treatment complications
• Prior treatment with immune checkpoint blockade therapies, including anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies
• Treatment with systemic immunostimulatory agents (including but not limited to interferons [IFNs], interleukin [IL]-2) within 6 weeks or five half- lives of the drug, whichever was shorter, prior to day 1
• Signs or symptoms clinically significant of infection within 2 weeks prior to day 1
• Any other systemic anti-cancer treatment (including investigational agents) within 4 weeks prior to the first dose of study drug. Note: Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible