Neoadjuvant Pembrolizumab in Combination With Gemcitabine Therapy in Cis-eligible/Ineligible UC Subjects

Inclusion Criteria

• Be willing and able to provide written informed consent for the trial.
• Over 18 years of age on day of signing informed consent.
• ECOG PS ≤ 2; please see protocol for specific details regarding ECOG PS for each cohort.
• Have histologically confirmed muscle invasive disease of the urinary bladder. For subjects who have tumors limited to the upper tract including renal pelvis or ureters, muscle invasive disease does not need to be pathologically proven, and a CT urogram must be performed (MRI is not acceptable to meet this criterion). To be eligible, subjects with upper tract tumors of the renal pelvis and ureter(s) must meet a high risk assessment defined as: tumor ≥ 1cm and/or hydronephrosis and/or high grade pathology and/or multifocal disease, where a radical NU approach to treat localized disease is warranted.
• Histology must be urothelial carcinoma (transitional cell carcinoma) or urothelial carcinoma with mixed histology/features.
• Clinical stage cT2-4aN0M0. Please see exclusion criteria for acceptable N0 determination/lymph node size.
• Have a surgical evaluation that documents the plan for multimodality therapy with a consolidative radical cystectomy or nephroureterectomy.

NOTE on surgical intent: Criteria for acceptable surgical risk are not defined and per treating urologist. Minimum guidance on surgical intent includes subjects who do not have significant cardiovascular disease such as NHYA class III or IV heart failure, unstable arrhythmias or angina, active CAD, and/or EF 1 year.

• Male subjects must agree to use a barrier method of male contraception starting with the first dose of study therapy and through 120 days after the last dose of study therapy.

COHORT I - CISPLATIN-ELIGIBLE:

In addition to the inclusion criteria listed above, Cohort I subjects must satisfy all of the following criteria:

• Glomerular filtration rate (GFR) or creatinine clearance (Ccr) ≥ 50 mL/min. (24 hour urine preferred). The cisplatin dose will be split over two days for values between 50-59 mL/min
• ECOG PS 0, 1 (and not 2)
• Hearing impaired ≤ grade 1 (may or may not be enrolled in a monitoring program)
• Peripheral neuropathy ≤grade 1

COHORT II - CISPLATIN-INELIGIBLE:

In addition to the inclusion criteria listed above, Cohort II subjects must also meet any ONE of the following criteria:

• GFR or Ccr: 30-49 (24 hour urine preferred).
• ECOG PS 2
• Hearing impaired ≥grade 2 as assessed by treating physician (may or may not be enrolled in a monitoring program).
• Peripheral neuropathy of Grade 2-4

Exclusion Criteria

Subjects may not have any of the following:

• A non-surgical approach recommended by the treating urologist due to any reason. Criteria for surgical intent are not defined and, rather, suitability is determined and documented by the subject's treating urologist. Minimum guidance on surgical intent includes subjects who do not have significant cardiovascular disease such as NHYA class III or IV heart failure, unstable arrhythmias or angina, active CAD, and/or EF<25%. Specific cardiopulmonary diagnostic testing to determine surgical intent is not required and per treating urologist or oncologist discretion.
• Has abdomino-pelvic short axis lymph node of ≥15mm without biopsy. NOTE: A subject with a staging biopsy proving a non-neoplastic process/N0 will meet inclusion.
• Subjects with disease that is limited to the upper tract urothelial cancer and is considered low risk defined as: unifocal disease and tumor size <1cm, and low grade cytology, and without an invasive aspect on CT-urography.
• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 28 days prior to study registration.
• Has a diagnosis of immunodeficiency or received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration. Subjects on steroids for physiologic replacement due to a non-cancer re