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

OUTLINE: This is a multi-center study. INVESTIGATIONAL TREATMENT: Phase Ib Dose-Finding Cohort I Cisplatin-Eligible: Phase Ib is a 3+3 design for the cisplatin-eligible group only. Cisplatin-eligible subjects receive: gemcitabine 1000mg/m2 IV D1 and D8 every 21 days repeated for 4 cycles; cisplatin 70mg/m2 IV D1 and D8 every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days). Pembrolizumab will be given every 3 weeks for 5 doses, with a starting dose of 200 mg. NOTE: the last dose of pembrolizumab falls on what would be D8 of a 5th 'chemo' cycle, however gemcitabine/cisplatin is NOT GIVEN. Phase II Arm A: Cohort I Cisplatin-Eligible: Cisplatin-eligible subjects receive: gemcitabine 1000mg/m2 IV D1 and D8 every 21 days repeated for 4 cycles; cisplatin 70mg/m2 IV D1 and D8 every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days). Pembrolizumab at recommended phase II dose (RP2D) is given every 3 weeks for 5 doses starting with C1D8. NOTE: the last dose of pembrolizumab falls on what would be day 8 of a 5th 'chemo' cycle, however gemcitabine/cisplatin is NOT GIVEN. Cohort I treatment with gemcitabine and cisplatin will continue for a maximum of 4 cycles (cycle = 21days). Phase II Arm B: Cohort II: Cisplatin-ineligible subjects receive gemcitabine 1000mg/m2 IV D1, D8 and D15 every 28 days, repeated for 3 cycles. Pembrolizumab at RP2D is given every 3 weeks for 5 doses starting with C1D8. NOTE: due to the timing of gemcitabine cycles every 4 weeks, and every three week dosing of pembrolizumab, there are two doses of pembrolizumab given during cycle 2: D1 and D22. Additionally, the last dose of pembrolizumab falls on what would be D8 of a 4th 'chemo' cycle; however gemcitabine is NOT GIVEN. Cohort II treatment with gemcitabine will continue for a maximum of 3 cycles (cycle = 28 days) Subjects will then have surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy. Eastern Cooperative Oncology Group (ECOC) performance status: 0-1 for cisplatin-eligible subjects; 0-2 for cisplatin-ineligible subjects. Demonstrate adequate organ function as defined by the following laboratory values at study entry. All screening labs should be performed within 28 days of C1D1. Hematopoetic: * Absolute neutrophil count (ANC) ≥1,500 /mcL * Absolute lymphocyte count ≥350 mcL * Platelets ≥100,000 / mcL * Hemoglobin ≥9 g/dL or ≥5.6 mmol/L Renal: * Measured or calculated creatinine clearance ≥30 mL/min Hepatic: * Serum total bilirubin ≤ 1.25 X ULN OR ≤ 2.5 x ULN for subjects with Gilbert's disease * Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤ 2 X ULN Coagulation: * International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy and as long as PT or PTT is within therapeutic range of intended use of anticoagulants