Risk Enabled Therapy after Neoadjuvant Immunochemotherapy for the Treatment of Bladder Cancer

Inclusion Criteria

• Male or female patients >= 18 years
• Primary urothelial or predominantly urothelial carcinoma of the bladder confirmed from pathology report. Patients with some component of variant histology mixed with predominant urothelial carcinoma will be allowed. Upper tract urothelial carcinoma patients are not allowed
• Urothelial carcinoma of the prostatic urethra in men is allowed
• Histologic evidence of muscularis propria invasion
• American Joint Committee on Cancer (AJCC) clinical stage T2-T3 N0M0
• No radiographic evidence of lymph node positive disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (>= 15 mm short axis diameter). Lymph node positive disease is defined as clinical lymphadenopathy on staging computed tomography (CT) or magnetic resonance imaging (MRI) greater than 1.4 cm in the short axis. If a lymph node is greater than 1.4 cm, it has to be biopsy proven negative for the patient to be eligible
• No metastatic disease (M0)
• Eastern Cooperative Oncology Group (ECOG) performance status 0, or 1
• Left ventricular ejection fraction >= 50% by multigated acquisition scan (MUGA) or echocardiogram (ECHO) within 6 months of study entry
• Negative pregnancy test in women of child bearing potential within 24 hours of study registration. If the pregnancy test is positive, the patient must not receive protocol treatment and must not be enrolled in the study
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin =< institutional upper limit of normal (ULN). If a patient has known Gilbert’s disease, an elevated bilirubin is allowed
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional ULN
• Creatinine clearance >= 50 mL/min (calculated using the Cockcroft-Gault formula or measured with 24 hour urine collection)
• Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document

Exclusion Criteria

• Any component of small cell histology
• Prior systemic chemotherapy or radiation therapy for urothelial carcinoma or cytotoxic chemotherapy for another malignancy within 1 year of study entry are ineligible. Patients who received immunotherapy for non-muscle invasive bladder cancer will be excluded
• Has a known additional malignancy that has had progression or has required active treatments in the last three years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with surgery is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; prostate specific antigen (PSA) undetectable for 1 year while off androgen deprivation therapy. Patients on active surveillance for low grade prostate cancer are allowed to participate
• Patients who have received experimental agents within 4 weeks of study entry
• Patients who have received doxorubicin based treatment in the past
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to methotrexate, vinblastine, doxorubicin or cisplatin or other agents used in the study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined by current oral or intravenous antibiotic therapy), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study due to the potential for teratogenic or abortifacient effects of cytotoxic chemotherapy
• Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cytotoxic chemotherapy. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Patients with hydronephrosis that has not been addressed with a documented assessment (i.e. normal glomerular filtration rate [GFR], no intervention necessary) or an intervention such as placement of a stent or nephrostomy tube
• Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled or topical steroids and adrenal replacement steroid doses < 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease. Use of steroids as pre-medication for contrast allergy prior to PET scans or CT scans is permitted. It is acceptable to use steroids as pre-medication for AMVAC
• 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 antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
• Prior treatment with CD137 agonists, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrollment