Adaptive RADiation Therapy With Concurrent Sacituzumab Govitecan (SG) for Muscle Invasive Bladder Cancer

Inclusion Criteria:

* Participants must have histologically or cytologically confirmed muscle-invasive bladder cancer (MIBC) (T2-T4aN0M0). Participants with mixed urothelial carcinoma will be eligible for the trial, except for small cell or neuroendocrine component
* Participants must have received no prior systemic chemotherapy for this disease. Participants must refuse conventional radio-sensitizing chemotherapy, (and/or) must not be eligible for or refuse cystectomy while on study Participants may receive cystectomy following the end of treatment (EOT)/ Safety Visit if deemed necessary by their clinical team while still in follow-up.
* Performance status: ECOG Performance status ≤ 2
* Participants must have normal organ and marrow function as defined below:

  * Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase \[SGOT\]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 x laboratory upper limit of normal (ULN)
  * Total serum bilirubin ≤ 2.0 x ULN
  * Absolute neutrophil count (ANC) ≥ 1500/μL
  * Platelets ≥ 100,000/μL
  * Hemoglobin ≥ 9.0 g/dL
  * Serum calcium ≤ 12.0 mg/dL
  * Calculated Creatinine Clearance ≥ 30 mL/min. Calculated using Cockcroft-Gault formula: Creatinine Clearance = \[\[140 - age(yr)\] multiplied by body weight(kg)\]/ \[72 multiplied by serum Cr(mg/dL)\] (multiply total by 0.85 for women).
* Participants must have adequate baseline bladder function to warrant bladder preservation as assessed by the treating provider, including absence of bilateral hydronephrosis or acute obstruction related to bladder tumor after TURBT. Unilateral hydronephrosis is permitted.
* Participants must undergo a TURBT within ≤ 60 days prior to treatment start. In a situation where a participant is referred from an outside site to the Cleveland Clinic Foundation, participant must have a repeat cystoscopy by the urologist who will be following the participant on the clinical trial to assess the adequacy of the prior TURBT. Participant may then undergo repeat TURBT if deemed necessary as standard of care by the treating urologist.
* Participants may have either completely or partially resected tumors as long as the treating urologist attempted maximal resection.
* Participant must undergo radiological staging within 60 days prior to treatment start. Imaging of chest, abdomen, and pelvis must be performed using CT or MRI. Participants must not have evidence of T4b and/or N1-3 dT4bN1-3 disease. Eligibility is based on review by Cleveland Clinic Foundation (CCF) radiology department and/or PI.
* Participants must not have had urothelial carcinoma or any histological variant at any site outside of the urinary bladder within the previous 24 months except Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract including renal, pelvis, and ureter if the participant had undergone complete nephroureterectomy.
* Participants must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Participants receiving or utilizing any other investigational agents or devices.
* Has received prior pelvic / local radiation therapy for MIBC or any other cancer type.
* Has received any prior systemic treatment, chemoradiation, and / or radiation therapy for MIBC or non-muscle-invasive bladder cancer (NMIBC). Note: Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted.
* Has diagnosed Bilateral hydronephrosis.
* Has limited bladder function as noted by a provider, with frequency of small amounts of urine, urinary incontinence including stress/urge, requires self-catheterization or a permanent indwelling catheter.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to SG or any of its' components.
* Participants with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant or breastfeeding women are excluded from this study because SG and radiation effects during pregnancy have 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 SG, breastfeeding should be discontinued if the mother is treated with Sacituzumab Govitecan.
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.

Note: Participants who have entered the Follow-up Phase of an investigational study may participate if it has been 4 weeks after the last dose of the previous investigational agent.

* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.