Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in cisplatin-eligible patients (pts) with muscle invasive bladder cancer (MIBC). An unmet need exists in cisplatin-ineligible pts with MIUC who are offered upfront surgery. Neoadjuvant immune checkpoint inhibitors (ICIs) have been demonstrated to be safe and active although the benefit may not extend to the majority of pts. The combination of GCa and an ICI has been demonstrated to be safe and active in cisplatin-ineligible metastatic urothelial carcinoma. In the neoadjuvant setting, combination GCa and an ICI may improve outcomes across a broad group of MIUC by delivering early systemic therapy to pts with cisplatin-ineligible MIUC. We hypothesized that the combination of GCa and avelumab, a PD-L1 inhibitor, may improve pathologic complete remissions (pCR) and long-term outcomes compared to upfront surgery for MIUC (S2011, NCT04871529). Methods: This multicenter, randomized (1:1), open-label phase II trial is comparing the combination of GCa and avelumab (Arm A) as neoadjuvant therapy vs. upfront surgery (Arm B) for pts with cisplatin-ineligible MIUC including MIBC and high-risk upper tract urothelial carcinoma (UTUC). Adjuvant therapy following radical cystectomy, nephroureterectomy or ureterectomy is deferred to investigator discretion in both arms. Eligible pts include those with MIBC or high-grade UTUC with a predominant urothelial component who are cisplatin-ineligible (≥1 of: Zubrod performance status [PS] = 2, creatinine clearance [CrCl] 30 to < 60 ml/min, neuropathy > grade 1, hearing loss > grade 1, congestive heart failure > grade 2). The primary objective is pCR. The stratification factors include clinical stage (cT2N0M0 vs cT3-4aN0M0), Zubrod-PS (0-1 vs 2), CrCl (30 to < 60 vs ≥ 60 ml/min). With 178 evaluable pts, the trial will have a power of 90% (using a 1-sided alpha 0.05) to detect pCR rate improvement from 15% to 35%. The secondary objectives are toxicities, resectability rates, surgical complications, event-free survival (EFS) and overall survival (OS). Correlative studies include tumor molecular profiling, blood immune studies, circulating tumor-DNA profiling and radiomics. Arm A receives gemcitabine 1000 mg/m² IV days 1, 8 every 3 weeks x 4 cycles, carboplatin AUC 4.5 (escalated to AUC 5 from cycle 2 if tolerated in cycle 1) IV day 1 every 3 weeks x 4 cycles and avelumab 800 mg IV day 1 every 2 weeks x 6 cycles. Surgery is performed 4-8 weeks after the last neoadjuvant administration. The trial is funded by NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180868, and in part by EMD Serono, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer. Clinical trial information: NCT04871529.