Nivolumab with or without Urelumab before Surgery in Treating Patients with Muscle-Invasive Bladder Urothelial Cancer

Inclusion Criteria

• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder defined as T2-T4 stage; mixed histologies are acceptable provided urothelial carcinoma is the predominant histology (>= 50%); patients with > 50% non- urothelial carcinoma histologies or any component of small cell carcinoma are not eligible; resectable clinical node-positive patients are eligible provided the lymph nodes are confined to the true pelvis and are within the planned surgical lymph node dissection template
• Sufficient baseline tumor tissue available to perform tumor infiltrating CD8+ T-cell density assessment; (NOTE: The actual CD8+ T-cell density assessment does not need to be performed prior to registration, however the slides must be reviewed by the local pathologist at the treating site [at a minimum] prior to registration to ensure that adequate tissue will be available for the pre-treatment tumor infiltrating CD8+ T-cell density assessment)
• Medically fit to undergo cystectomy
• Electively refusing cisplatin-based neoadjuvant chemotherapy OR ineligible to receive cisplatin-based neoadjuvant chemotherapy based upon at least one of the following criteria: * Creatinine clearance < 60 ml/min * Eastern Cooperative Oncology Group (ECOG) performance status = 2 * Grade >= 2 hearing loss * Grade >= 2 neuropathy * New York Heart Association class III heart failure
• Absolute neutrophil count (ANC) >= 1.5 K/mm^3 (must be stable off any growth factor within 4 weeks of first study drug administration)
• Platelets >= 100 K/mm^3 (transfusion to achieve this level is not permitted within 2 weeks of first study drug administration)
• Hemoglobin (Hgb) >= 9 g/dL
• Serum total bilirubin: =< 1.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN
• Serum creatinine clearance (CrCl) >= 30 mL/min using the Cockcroft- Gault equation
• Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria

• Patients with locally advanced unresectable or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 28 days prior to study registration; the required radiographic imaging includes: * Abdomen/Pelvis – computed tomography (CT) scan * Chest – chest x-ray or CT scan
• Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma; (NOTE: Patients with history of non-invasive [Ta, Tis] upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment [i.e. cytology, biopsy, imaging] that demonstrates no evidence of residual disease are eligible)
• Patients with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer; patients that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment
• Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies =< 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
• Patients who have received prior therapy with immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4) or immune costimulatory molecules (e.g. anti-CD137, anti-OX40, anti-GITR) directed agents
• Patients who have had radiotherapy =< 4 weeks prior to starting study drug, or who have not recovered from radiotherapy toxicities
• Patients who have undergone major surgery (e.g. intra-thoracic, intra- abdominal or intra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior to starting study drug, or patients who have had minor procedures (i.e. transurethral resection of bladder tumor [TURBT]), percutaneous biopsies or placement of vascular access device =< 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
• Patients with history of alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis. (NOTE: Patients with radiographic evidence of steatohepatitis are excluded unless a liver biopsy is obtained demonstrating no evidence of alcoholic or non-alcoholic steatohepatitis.)
• Patient with history of prior solid organ or allogeneic bone marrow transplant
• Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: * Clinically significant cardiac diseases, including any of the following: ** History or presence of serious uncontrolled ventricular arrhythmias ** Clinically significant resting bradycardia ** Any of the following within 3 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE) ** Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mmHg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication(s) * Cirrhosis, chronic active hepatitis or chronic persistent hepatitis * Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) * Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy; usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted; for questions, please consult the study chair * Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
• Pregnant or breast-feeding women
• Women of child-bearing potential, who are biologically able to conceive, and not employing two forms of highly effective contraception; highly effective contraception must be used throughout the trial and up to 7 months after the last dose of study drug (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device); women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test =< 14 days prior to starting study drug
• Fertile males not willing to use contraception, as stated above
• Patients unwilling or unable to comply with the protocol