Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic urothelial carcinoma; urothelial cancer derived from the bladder, ureter or upper tract is permitted
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm) with conventional techniques or as ≥ 10 mm (≥ 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Patients must have access to archival tumor tissue for proposed correlative studies; these may be derived from transurethral resection of bladder tumors (TURBT), cystectomy, or biopsy; if archival tissue is not available for proposed correlatives, patients may be enrolled at the discretion of the study principal investigator (PI) (SKP)
• No prior cytotoxic chemotherapy for metastatic disease
• At least 12 months have elapsed since platinum-based peri-operative treatment
• Karnofsky ≥ 70% (Eastern Cooperative Oncology Group [ECOG] performance status 0-1)
• Life expectancy of greater than 3 months
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x institutional upper limit of normal
• Creatinine clearance ≥ 50 mL/min by either measured or calculated clearance
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of VX-970 administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Radiotherapy within 4 weeks of protocol therapy
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to VX-970, cisplatin, or gemcitabine
• Concomitant administration with strong inhibitors or inducers of CYP3A4 should be avoided; it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with VX-970; these potential risks may also apply to other agents used in this study
• Patients with ≥ grade 2 neuropathy