Gemcitabine Hydrochloride and Eribulin Mesylate in Treating Patients With Bladder Cancer That is Advanced or Cannot Be Removed by Surgery

• Patients must have locally advanced or metastatic predominantly urothelial carcinoma of the bladder, ureter, or urethra that is not amenable to curative surgical treatment
• Patients must have histologically confirmed predominantly urothelial carcinoma of the bladder, ureter, or urethra
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 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 with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

• Patients must be ineligible for treatment with cisplatin, based on one of:

  • Calculated creatinine clearance (CrCl) >= 30 and \< 60 mL/min (Cockcroft-Gault)
  • CTCAE grade (Gr) >= 2 hearing loss
  • CTCAE Gr >= 2 neuropathy
• Patients must not have received prior systemic therapy for their advanced cancer; prior intravesical therapy completed 4 weeks prior to enrollment and adjuvant/neoadjuvant chemotherapy completed more than 6 months prior to diagnosis of advanced disease are permitted
• Zubrod performance status =\< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 3 months
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin \< 1.5 times the upper limit of normal (x ULN) for the institution
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =\< 3 x institutional upper limit of normal
• Creatinine clearance; calculated creatinine clearance (CrCl) >= 30 mL/min and \< 60 mL/min (Cockroft-Gault) unless the patient qualified based on hearing loss or neuropathy
• 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 4 months after completion of gemcitabine and eribulin administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients with a small cell component in their histology are excluded
• Patients who have had chemotherapy for the treatment of the advanced or unresectable urothelial cancer of the bladder are not eligible; patients who were previously treated for local disease must not have received radiotherapy or chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study and must have recovered from adverse events due to agents administered more than 4 weeks earlier; patients who have received neoadjuvant or adjuvant chemotherapy must have completed treatment at least 6 months prior to diagnosis of metastatic disease
• Patients who are receiving any other investigational agents
• Patients with known brain metastases should be excluded from this clinical trial
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine and eribulin
• Uncontrolled intercurrent illness including, but not limited to, a second cancer diagnosis within the past 5 years, or a cancer undergoing any treatment, 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 eribulin and gemcitabine
• Human immunodeficiency virus (HIV)-positive patients with inadequate cluster of differentiation (CD)4 counts or those who are on combination antiretroviral therapy with strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) effects are ineligible for this trial
• Patients with baseline corrected QT (QTc) prolongation greater than grade 1 are excluded from this study; patients with grade 1 QTc elevation are eligible but must be monitored with electrocardiogram (ECG) (EKG) exams, for the first 3 cycles of treatment; eribulin time to maximum concentration (Cmax) after infusion is about 10 minutes, and half life is 40 minutes; ECG (EKG) should be performed between 10 to 40 minutes after eribulin administration (on day 1 and day 8 of treatment); continued ECG (EKG) monitoring beyond cycle 3 can be done at the discretion of the treating physician
• Patients with congenital long QT syndrome are excluded from this study
• Other medications known to prolong QT interval should be discontinued and if not possible, patient is excluded from this study