Enfortumab Vedotin, Pembrolizumab, and Quemliclustat for unresectable or metastatic urothelial cancer

Inclusion Criteria:

* Participants must be at least 18 years of age on the day of signing informed consent. Participant provides written informed consent for trial
* Participants must have previously untreated locally advanced or metastatic bladder cancer including bladder cancer \[stage IIIB: T1-T4N2-3M0, stage IVa: T4bAnyNM0 or AnyTAnyNM1a, and stage IVB: AnyTAnyNM1b clinical stage per American Joint Commission on Cancer (AJCC)\] or renal pelvis or ureter cancer \[stage IV: T4Nx-0M0, AnyTN1-2M0, AnyTAnyNM1 clinical stage per AJCC\]. Lymph node with ≥ 15 mm short axis or biopsy-positive for carcinoma will be considered pathologically enlarged and measurable
* Participants must have either conventional urothelial carcinoma or urothelial carcinoma variants. A review of pathology by a local expert genitourinary (GU) pathologist is required to confirm the diagnosis. Any component (%) of non-conventional urothelial noted on tumor specimen is allowed for only histologic subtypes listed below in up to 20% of participants enrolled in this study.

  * Urothelial carcinoma with squamous differentiation
  * Urothelial carcinoma with glandular differentiation
  * Urothelial carcinoma with trophoblastic differentiation
  * Nested urothelial carcinoma
  * Tubular and microcystic urothelial carcinoma
  * Micropapillary urothelial carcinoma
  * Lymphoepithelioma-like urothelial carcinoma
  * Plasmacytoid urothelial carcinoma
  * Sarcomatoid urothelial carcinoma
  * Giant cell urothelial carcinoma
  * Lipid-rich urothelial carcinoma
  * Clear cell (glycogen rich) urothelial carcinoma
  * Poorly differentiated urothelial carcinoma
  * Squamous cell neoplasms including pure squamous cell carcinomas, verrucous carcinomas and squamous cell papilloma
* Measurable disease by RECIST v 1.1
* Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
* Available baseline fresh biopsy tissue sample obtained in the protocol RG1712006 or RG1125031 though clinically indicated procedures or participants must be willing to undergo a baseline research biopsy when safe and feasible
* Participant must have an estimated life expectancy of at least 3 months
* Hemoglobin ≥ 9 g/dl
* Absolute neutrophil count: ≥ 1500/ µL
* White blood cell count: ≥ 3000/µL
* Absolute lymphocyte count: ≥ 1000/µL
* Platelet count: ≥ 100.000/µL (without transfusion support)
* Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 2.5 x upper limit of normal (ULN)
* Total bilirubin: ≤ 1.5 mg/dl except for patients with Gilbert's syndrome who must have a total bilirubin ≤ 3 mg/dl
* Creatinine clearance: ≥ 30 ml/min/1.73m\^2 by the method of Chronic Kidney Disease Epidemiology Collaboration (CKI-EPI) or ≥ 30 ml/min by the method of 24 hour (h) clearance of creatinine calculation
* International Normalized Ratio (INR): \< 1.5

Exclusion Criteria:

* Participants who are receiving any other investigational agents or concurrent anticancer treatment. Participants must have adequate treatment washout period before treatment, defined as: Major surgery (≥ 4 weeks), palliative radiation therapy (≥ 1 weeks from completion of treatment if they have recovered from the acute toxic effect of radiotherapy), prior adjuvant immunotherapy (≥ 4 weeks)
* Participants whose tumors have any % neuroendocrine or small cell histology, glandular neoplasms, urachal carcinomas, tumor of mullerian type, mesenchymal tumors or urothelial tract hematopoietic and lymphoid tumors
* Participants considered to be medically unfit for EV-P regimen as per Investigator discretion
* Participants with concurrent use of systemic steroids (within 10 days of enrollment), except for physiologic doses of systemic steroid replacement or local (topical, nasal, intraarticular or inhaled) steroid use
* Participants who have experienced disease progression following neoadjuvant or adjuvant systemic therapy within 12 months prior to enrollment will not be eligible
* Patients with Fridericia's corrected QT interval (QTcF) interval at screening of \> 480 milliseconds.

  * Note: For any QTcF \> 480 milliseconds on initial electrocardiogram (ECG), a follow-up ECG will be performed to confirm QTcF interval prolongation and exclude the patient from this study
* Participants with active systemic autoimmune disease (e.g., lupus erythematosus, rheumatoid arthritis, Addison's disease, autoimmune disease associated with lymphoma, inflammatory bowel disease). Participants with autoimmune endocrine disorders controlled by medical management (e.g. thyroid disorders, type 1 diabetes, or adrenal insufficiency) will not be excluded
* Participants who are known to be serologically positive for human immunodeficiency virus (HIV) and a CD4 count \< 350 cells/microliter
* Participants with known active hepatitis (i.e. Hepatitis B or C). Prior hepatitis (Hep) C infection is allowed as long as polymerase chain reaction (PCR) test is negative
* Participants with clinically inactive brain metastases may be included. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole-brain radiation therapy and study treatment
* Participants with new or progressive brain metastases (less or equal of 1 cm of larger diameter) are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required for at least 4 weeks (or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis (discussion) by the participant and the investigator favors participation in the clinical trial. Patients with leptomeningeal disease will be excluded
* History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy of assessment of the investigational regimen are eligible for this trial
* Woman of childbearing potential with positive serum pregnancy test within 72 hours prior to enrollment. Active lactation is an exclusion criterion