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

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed muscle-invasivebladder cancer (MIBC) (T2-T4aN0M0). Participants with mixed urothelial carcinomawill 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) mustnot be eligible for or refuse cystectomy while on study Participants may receivecystectomy following the end of treatment (EOT)/ Safety Visit if deemed necessary bytheir 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 pyruvictransaminase [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-Gaultformula: Creatinine Clearance = [[140 - age(yr)] multiplied by bodyweight(kg)]/ [72 multiplied by serum Cr(mg/dL)] (multiply total by 0.85 forwomen).

• Participants must have adequate baseline bladder function to warrant bladderpreservation as assessed by the treating provider, including absence of bilateralhydronephrosis or acute obstruction related to bladder tumor after TURBT. Unilateralhydronephrosis is permitted.

• Participants must undergo a TURBT within ≤ 60 days prior to treatment start. In asituation where a participant is referred from an outside site to the ClevelandClinic Foundation, participant must have a repeat cystoscopy by the urologist whowill be following the participant on the clinical trial to assess the adequacy ofthe prior TURBT. Participant may then undergo repeat TURBT if deemed necessary asstandard of care by the treating urologist.

• Participants may have either completely or partially resected tumors as long as thetreating urologist attempted maximal resection.

• Participant must undergo radiological staging within 60 days prior to treatmentstart. 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. Eligibilityis based on review by Cleveland Clinic Foundation (CCF) radiology department and/orPI.

• Participants must not have had urothelial carcinoma or any histological variant atany site outside of the urinary bladder within the previous 24 months exceptTa/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 awritten 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 cancertype.

• Has received any prior systemic treatment, chemoradiation, and / or radiationtherapy for MIBC or non-muscle-invasive bladder cancer (NMIBC). Note: Priortreatment for NMIBC with intravesical instillation therapy such as BCG orintravesical chemotherapy is permitted.

• Has diagnosed Bilateral hydronephrosis.

• Has limited bladder function as noted by a provider, with frequency of small amountsof urine, urinary incontinence including stress/urge, requires self-catheterizationor a permanent indwelling catheter.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to SG or any of its' components.

• Participants with uncontrolled intercurrent illness including, but not limited toongoing or active infection, symptomatic congestive heart failure, unstable anginapectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situationsthat would limit compliance with study requirements.

• Pregnant or breastfeeding women are excluded from this study because SG andradiation effects during pregnancy have potential for teratogenic or abortifacienteffects. Because there is an unknown, but potential risk for adverse events innursing infants secondary to treatment of the mother with SG, breastfeeding shouldbe discontinued if the mother is treated with Sacituzumab Govitecan.

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof 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 laboratoryabnormality that might confound the results of the study, interfere with theparticipant's participation for the full duration of the study, or is not in thebest interest of the participant to participate, in the opinion of the treatinginvestigator.