Pembrolizumab in Muscle-invasive Bladder Cancer

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

• Written informed consent and HIPAA authorization for release of personal healthinformation prior to registration. NOTE: HIPAA authorization may be included in theinformed consent or obtained separately.

• Age ≥ 18 years at the time of consent.

• ECOG Performance Status of ≤ 1 within 28 days prior to registration.

• Histological evidence of clinically localized muscle-invasive urothelial cancer ofthe bladder. Clinical stage cT2-3N0M0. N0 will be considered the absence ofradiographically enlarged lymph nodes on baseline imaging. Patients with lymph nodes <1 cm in long axis on imaging may be eligible but must be discussed with the sponsorinvestigator.

• Have undergone a standard of care maximal transurethral resection of bladder tumor ≤ 60 days prior C1D1. Maximal TURBT is defined as a macroscopically complete resectionof bladder tumor when safely possibly per the treating urologist. Patients whocannot safely undergo maximal TURBT as per their treating urologist are eligible forenrollment but should be discussed with the sponsor investigator.

• All subjects must have adequate transurethral resection of bladder tumor tissueavailable for submission (i.e., at least 15 unstained slides or paraffin block)identified during screening. This tissue can be from the maximal restaging TURBT, aprior diagnostic TURBT revealing muscle-invasive bladder cancer, or both specimens.Subjects without available archival tissue must be discussed with thesponsor-investigator.

• Decline cisplatin-based neoadjuvant chemotherapy or be consideredcisplatin-ineligible based on at least one of the following modified criteria (asECOG 0-1 is required for eligibility):

• Creatinine clearance < 60 mL/min (but ≥ 30 mL/min)

• Grade ≥ 2 hearing loss (per CTCAE criteria v5)

• Grade ≥ 2 neuropathy (per CTCAE criteria v5)

• New York Heart Association Class III heart failure

• Demonstrate adequate organ function as defined below. All screening labs to beobtained within 28 days prior to registration.

• Hematological

• Absolute Neutrophil Count (ANC): ≥ 1.5 x 10^9/L

• Hemoglobin (Hgb): ≥ 9 g/dL

• Platelets: ≥ 100 x 10^9/L

• Renal

• Creatinine OR: Creatinine ≤ 1.5 × ULN OR

• Calculated creatinine clearance: creatinine clearance ≥ 30 mL/min

• Hepatic

• Bilirubin: ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants withtotal bilirubin levels > 1.5 × ULN

• Aspartate aminotransferase (AST): ≤ 2.5 × ULN

• Alanine aminotransferase (ALT): ≤ 2.5 × ULN

• Women of childbearing potential (WOCP) must have a negative serum or urine pregnancytest a maximum of 24-hours before the first dose of study drug. If the urine test ispositive or cannot be confirmed as negative, a serum pregnancy test will berequired. WOCBP must agree to use contraception.

• A male participant must agree to use contraception.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

• Prior systemic chemotherapy for muscle-invasive urothelial cancer of the bladder.

• Prior malignancy active within the previous 2 years except for locally curablecancers that have been apparently cured. Patients with intermediate or lower riskprostate cancer as defined by the National Comprehensive Cancer Network (NCCN) riskstratification guidelines may be eligible for enrollment.

• Prior radiation therapy for bladder cancer.

• Active infection requiring systemic therapy.

• Has a known history of Hepatitis B or C. NOTE: Patients with a past or resolved HBVinfection (defined as the presence of hepatitis B core antibody [anti-HBc] andabsence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody areeligible only if polymerase chain reaction is negative for HCV RNA. NOTE: no testingfor Hepatitis B and Hepatitis C is required unless mandated by local healthauthority.

• Has a known history of Human Immunodeficiency Virus (HIV) infection. NOTE: notesting for HIV is required unless mandated by local health authority.

• Has a known history of active TB (Bacillus Tuberculosis).

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study).

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg,CTLA-4, OX 40, CD137).

• Has received a live or live-attenuated vaccine within 30 days prior to the firstdose of study drug. Administration of killed vaccines is allowed.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of itsexcipients.

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

• Has had an allogenic tissue/solid organ transplant.

• Is currently receiving an investigational agent or has received an investigationalagent or used an investigational device within 28 days of study registration.