Bladder Preservation or Cystectomy for MIBC

Inclusion Criteria:

* Patient must have signed written informed consent indicating understanding of the purpose of the study and willingness to participate prior to any protocol-related procedures, including screening evaluation.
* Participants must have histologically confirmed cT2-cT4aN0M0 urothelial (transitional cell) carcinoma of the bladder. Mixed histology is acceptable as long as there is a majority component of urothelial carcinoma.
* Availability of baseline archival tumor tissue obtained for molecular analysis and correlative studies
* Age ≥ 18 years
* Candidate for radical cystectomy
* Cisplatin eligible
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Participants infected with human immunodeficiency virus on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* Participants with evidence of chronic hepatitis B virus infection with an undetectable HBV viral load on suppressive therapy, if indicated, are eligible for this trial
* Participants with a history of hepatitis C virus (HCV) must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Participants with a prior or concurrent history of malignancy whose natural history of treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational protocol are eligible for this trial
* Participants must have adequate organ and marrow function as defined below:

  * Leukocytes ≥3,000/mcL
  * Hemoglobin ≥9.0 g/dL
  * Absolute neutrophil count ≥1,500/mcL
  * Platelets ≥100,000/mcL
  * International Normalized ratio ≤1.5 x institutional upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
  * Unless the patient is receiving anticoagulation therapy provided INR or PTT is within the therapeutic range of the intended anticoagulant
  * Total bilirubin ≤ institutional upper limit of normal (ULN)
  * This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician
  * AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN
  * Measured creatinine clearance ≥ 50 mL/min or calculated creatinine clearance 50mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
  * Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
  * Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)
* Evidence of post-menopausal status or negative urinary or serum pregnancy test for pre-menopausal female patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.

  * Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  * Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment.
* Patient is willing and able to comply with the protocol for the duration of the trial

Exclusion Criteria:

* Patients with urothelial carcinoma of the ureter, urethra, or renal pelvis
* Contraindication for bladder radiation
* Inoperable primary tumor
* Any previous systemic chemotherapy or radiotherapy for bladder cancer
* Inflammatory bowel disease
* Patients who are receiving or have received any other investigational agents within 6 months of study entry
* Child-Pugh class C hepatic impairment
* Receipt of the last dose of intravesical chemotherapy or biologic therapy ≤ 42 days (6 weeks) prior to the first dose of study drug for patients who have received prior intravesical chemotherapy or biologic therapy (e.g. BCG)
* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, unstable cardiac arrhythmia, symptomatic interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
* Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions, and requirements
* Pregnant women are excluded from this study because chemotherapy and radiation have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with chemotherapy, breastfeeding should be discontinued if the mother is treated with chemotherapy.