Background: Trilaciclib is an intravenous (IV) CDK4/6 inhibitor that has been shown to help protect hematopoietic stem and progenitor cells from chemotherapy (CT)-induced damage (myeloprotection) via transient cell cycle arrest. Trilaciclib is approved in the US to decrease the incidence of CT-induced myelosuppression (CIM) in adult patients with extensive-stage small cell lung cancer receiving certain treatment regimens. An exploratory phase 2 study (NCT02978716) in patients with triple-negative breast cancer showed improved overall survival (OS) in patients receiving trilaciclib prior to CT vs CT alone, regardless of PD-L1 expression. The aim of this exploratory, randomized, open-label, multicenter, phase 2 trial (PRESERVE 3; NCT04887831) is to assess whether trilaciclib administered with standard-of-care platinum-based CT and avelumab maintenance can improve antitumor efficacy and reduce CIM versus CT and avelumab without trilaciclib, in patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: Adult patients with measurable disease per RECIST v1.1, no prior systemic treatment for mUC, and ECOG performance status ≤2 will be randomized 1:1 to receive gemcitabine 1000 mg/m² plus cisplatin 70 mg/m² or carboplatin area under the curve 4.5 (± trilaciclib 240 mg/m² IV over 30 minutes, ≤4 hours prior to CT) in 21-day cycles. Patients will receive 4–6 cycles of CT. Those without progressive disease per RECIST v1.1 can receive avelumab 800 mg maintenance therapy (± trilaciclib) in 14-day cycles until disease progression, unacceptable toxicity, investigator/patient decision, or end of trial. Patients will be followed for survival. The sample size was calculated to support the primary endpoint of progression-free survival (PFS), using a stratified log-rank test accounting for two stratification factors (visceral metastasis and platinum agent [cisplatin/carboplatin]). 63 PFS events will be required to achieve 77% power to detect a hazard ratio of 0.6 with a 2-sided significance of 0.2, corresponding to a median PFS of 11.7 months for the trilaciclib arm. Assuming a 10-month enrollment period, final PFS analysis approximately 22 months after the first randomization, and 5% loss to follow-up, 90 patients are required for randomization. PFS will be analyzed in the intention-to-treat population. Secondary endpoints include objective response rate, disease control rate, PFS during maintenance, OS, multilineage myeloprotective effects, and safety/tolerability. Exploratory endpoints will assess pharmacodynamic parameters, including those related to immune-based mechanisms, and efficacy by CDK4/6-dependence. Enrollment opened in June 2021. As of September 29, 2021, 8 sites are open, and 1 patient randomized. Clinical trial information: NCT04887831.