This study evaluates the clinical benefit of TAS-102 in participants with metastatic urothelial carcinoma who are resistant to cisplatin or carboplatin front-line and checkpoint inhibitors as second line therapy. All participants will receive TAS-102 in oral form twice per day on Days 1-5 and Days 8-12 of each 28 day cycle.

Inclusion Criteria:

• Ability of participant to understand this study, and participant willingness to sign a written informed consent.
• Participants must have histologically or cytologically confirmed locally advanced unresectable or metastatic urinary bladder (urothelial) cancer. Participants with mixed histologies are permitted as long as transitional cell carcinoma is present in the pathological specimen.
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension
• Documented progression on or within 12 months of treatment with one previous platinum-containing regimen or ineligible to receive platinum-containing regimen. Neo-adjuvant or adjuvant platinum-based chemotherapy will be deemed to be first-line when participants progressed within 12 months of the last dose
• Documented progression on prior checkpoint inhibitor or ineligible to receive check-point inhibitor
• Adequate performance status, organ, and marrow function.
• Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence, or to use two forms of adequate contraception.
• Men of child-bearing potential must not father a child or donate sperm while on this study and for 6 months after their last study treatment

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks of enrollment/registration.
• Current or anticipated use of other investigational agents while participating in this study.
• Psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or breast feeding (if applicable).
• Patients with known brain metastases
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAS 102.
• Patients with HIV on anti-retro-viral therapy with thymidine kinase substrates, for example, stavudine, zidovudine, telbivudine.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. Undergoing active treatment for a co-existing malignancy with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, thyroid cancer or incidental prostate adenocarcinoma detected at radical cystectomy