Avelumab in Combination With Fluorouracil and Mitomycin or Cisplatin and Radiation Therapy in Treating Participants With Muscle-Invasive Bladder Cancer

Inclusion Criteria:

• Histologic proof of T2-T4a N0M0 (American Joint Committee on Cancer [AJCC] 8thedition) with predominant urothelial carcinoma. Mixed histologies are acceptableprovided urothelial carcinoma is the predominant histology. Small cell urothelialcarcinoma is excluded.
• Cystoscopy with maximal TURBT performed =< 70 days of study registration. NOTE: Bothcompletely resectable or partially resectable tumors are eligible as long as thetreating urologist attempted complete resection. Exam under anesthesia needs to beperformed and documented.
• Absolute neutrophil count (ANC) >= 1500/mm^3 =< 28 days prior to registration.
• Platelets (PLT) 100,000/mm^3 =< 28 days prior to registration.
• Total bilirubin =< 1.5 upper limit of normal (ULN) =< 28 days prior to registration.
• Aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x ULN for patients with liverinvolvement) =< 28 days prior to registration.
• Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN for patients with liverinvolvement) =< 28 days prior to registration.
• Hemoglobin (Hgb) >= 9 gm/dl =< 28 days prior to registration.
• Calculated creatinine clearance must be >= 30 ml/min using the Cockcroft-Gault formula =< 28 days prior to registration.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS 0, 1, 2).
• Ability to provide informed written consent.
• Willing to return to enrolling institution for follow-up (during the active monitoringphase of the study).
• Life expectancy >= 6 months.
• Negative serum pregnancy test done =< 14 days prior to registration, for women ofchildbearing potential only.

Exclusion Criteria:

• Patients with locally advanced unresectable (T4b) or metastatic urothelial carcinoma (N1M0-1) as assessed on baseline radiographic imaging obtained =< 70 days prior tostudy registration. The required radiographic imaging includes:
• Abdomen/pelvis computed tomography (CT) or magnetic resonance imaging (MRI) scan
• Chest x-ray or CT scan.
• Patients with concurrent urothelial carcinoma and/or related variants anywhere outsidebladder
• NOTE: Patients with history of non-invasive (Ta, Tis) upper tract urothelialcarcinoma that has been definitively treated with at least one post-treatmentdisease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidenceof residual disease are eligible.
• A prior or concurrent malignancy of any other site or histology unless the patient hasbeen disease-free for > 2 years prior to registration except for:
• Non-melanoma skin cancer and/or localized prostate cancer (T2 a or b , Gleason < 3+4) or carcinoma in situ of the uterine cervix which has been adequately treated =< 2 years prior to registration
• Or undergoing active surveillance per standard-of-care management (e.g., chroniclymphocytic leukemia Rai stage 0, prostate cancer with Gleason score =< 3+4, andprostate-specific antigen [PSA] =< 10 mg/mL, etc.).
• Patients who have received the last administration of an anti-cancer therapy includingchemotherapy, immunotherapy, and monoclonal antibodies =< 4 weeks prior toregistration, or who have not recovered from the side effects of such therapy.
• EXCEPTION: Except single dose intravesical chemotherapy administered after TURBT.
• Patients who have received prior therapy with immune checkpoint inhibitors (e.g.anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4, anti-TIM3) or immune co-stimulatorymolecules (e.g. anti-CD137, anti-OX40, anti-GITR) directed agents.
• Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal orintra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior toregistration, or who have not recovered from side effects of such procedure or injuryprior to registration.
• NOTE: Patients who have had minor procedures (i.e. TURBT) or percutaneousbiopsies prior to registration are eligible.
• Patients with history of cirrhosis, alcoholic or non-alcoholic steatohepatitis (NASH),auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis.
• Patient with history of prior solid organ or allogeneic bone marrow transplant.
• 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 =< 3 months prior to registration: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestiveheart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE).
• Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hgand/or diastolic blood pressure (DBP) >= 100 mm Hg, with or withoutanti-hypertensive medication(s).
• History of untreated human immunodeficiency virus (HIV)
• NOTE: There is no requirement to screen patients for HIV. Patients with historyof HIV infection are allowed if on effective highly active antiretroviral therapy (HAART) therapy and CD4 count more than 250.
• History of active hepatitis B infection
• NOTE: There is no requirement to screen patients for hepatitis B.
• 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.
• NOTE: Usage of non-steroidal anti-inflammatory medications (NSAIDS) for thetreatment of osteoarthritis and uric acid synthesis inhibitors for the treatmentof 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 unacceptablesafety risks or compromise compliance with the protocol.
• Pregnant or breast-feeding women.
• Women of child-bearing potential, who are biologically able to conceive, and notemploying two forms of highly effective contraception. Highly effective contraceptionmust be used throughout the trial and up to 8 weeks 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 notundergone a hysterectomy or who have not been naturally postmenopausal for at least 12consecutive months (i.e., who has had menses any time in the preceding 12 consecutivemonths), must have a negative serum pregnancy test =< 14 days prior to registration.
• Fertile males not willing to use contraception, as stated above.
• Patients unwilling or unable to comply with the protocol.
• Receiving any other investigational agent which would be considered as a treatment forthe primary neoplasm.
• Known prior severe hypersensitivity to investigational product or any component in itsformulations, including known severe hypersensitivity reactions to monoclonalantibodies (National Cancer Institute [NCI] Common Terminology Criteria for AdverseEvents [CTCAE] version [v] 5.0 grade >= 3).