Pemetrexed Disodium in Treating Patients With Previously Treated Metastatic Urothelial Cancer

Inclusion Criteria:

* Patients must have histological confirmation of metastatic urothelial carcinoma; patients must have sufficient tumor tissues for future MTAP testing and research; histological variants such as glandular, squamous, sarcomatoid, micropapillary, plasmacytoid, and small cell changes will not be allowed for this trial unless these tumors are MTAP-deficient
* All patients must have measurable disease and tumors of sufficient sizes for biopsy; in general, liver and lung lesions should be at least 1.0 cm, and patients with lymph node-only disease should have lesions of \>= 1.5 cm in shortest dimension; patients with disease confined to bone may be eligible if a measurable lytic defect is present; the study principal investigator (PI) is the final arbiter in questions related to measurability; patients with a three-dimensional mass or pelvic sidewall fixation on bladder examination under anesthesia are considered to have measurable disease
* Patients who have received any non-anti-folate containing neoadjuvant or systemic chemotherapy are eligible; any prior intravesical therapy, or immunotherapy is allowed
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 3 x upper limit normal (ULN), or =\< 5 x ULN if documented liver metastases are present
* Total bilirubin =\< 1.5 x ULN, except subjects with Gilbert's syndrome or liver metastases, who must have a baseline total bilirubin =\< 3.0 mg/dL
* Absolute neutrophil count (ANC) \>= 1500
* Platelets \>= 100,000
* Normal serum creatinine, or a creatinine clearance \>= 40 ml/min (either measured using a 24 hour urine, calculated using Cockroft-Gault, or estimated using the Modification of Diet in Renal Disease \[MDRD\] method from the National Kidney Disease Education Program \[NKDEP\] \[the method reported by M D Anderson Cancer Center (MDACC) laboratories\])
* Females of childbearing potential who are sexually active with a non-sterilized male partner and non-sterilized males must use a highly effective method of contraception for 28 days prior to the first dose of investigational product, and must agree to continue using such precautions for 180 days after the final dose of investigational product; cessation of contraception after this point should be discussed with a responsible physician
* Females of childbearing potential must also refrain from egg cell donation for 180 days after the final dose of investigational product;

  * Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause)
  * A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly; the acceptable methods of contraception are: barrier method (e.g. male condom with spermicide, copper T intrauterine device, or levonorgestrel-releasing intrauterine system - Mirena) or hormonal methods (e.g. implants, hormone shot or injection, combined pill, minipill, or patch); non-sterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from days 1-180 post last dose; in addition, they must refrain from sperm donation for 180 days after the final dose of investigational product
* The ability to interrupt nonsteroidal antiinflammatory drug (NSAIDS) 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed
* The ability to take folic acid, vitamin B12, and dexamethasone according to protocol

Exclusion Criteria:

* Primary central nervous system (CNS) malignancies or CNS metastases, including leptomeningeal metastases, are not allowed; subjects with previously treated brain metastases will be allowed if the brain metastases have been stable for at least 3 months following prior treatment (radiotherapy or surgery)
* Patients who received previous anti-folate-containing chemotherapy
* Any other malignancy from which the patient has been disease-free for less than 3 years, except for non-melanoma skin cancer, controlled localized prostate cancer, in situ carcinoma of any site
* Women who are pregnant or breastfeeding
* Presence of third space fluid which cannot be controlled by drainage; for patients who develop or have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before or during initiation of pemetrexed therapy, consideration should be given to draining the effusion prior to dosing; however, if, in the investigator's opinion, the effusion represents progression of disease, the patient should be discontinued from study therapy