• To determine the objective response rate for pralatrexate with concurrent vitamin B12 and folic acid supplementation in the treatment of patients with advanced or metastatic relapsed TCC of the urinary blad [ Time Frame: Study Duration ] [ Designated as safety issue: No ]
  

• To determine the duration of response, clinical benefit rate, progression-free survival (PFS), and overall survival (OS) in patients with advanced or metastatic relapsed TCC of the urinary bladder treated with pralatrexate. [ Time Frame: Study Duration ] [ Designated as safety issue: No ]
  
• To evaluate the safety and tolerability of administration of pralatrexate with concurrent vitamin B12 and folic acid supplementation in patients with advanced or metastatic relapsed TCC of the urinary bladder. [ Time Frame: Study Duration ] [ Designated as safety issue: Yes ]
  

This is a Phase 2, open-label, single-arm, multi-center study of pralatrexate administered concurrently with vitamin B12 and folic acid supplementation in patients with advanced or metastatic relapsed transitional cell carcinoma (TCC) of the urinary bladder.

The start of study treatment is defined as the initiation of pralatrexate treatment. All patients will receive pralatrexate over 1 hour on days 1 and 15 of a 4 week cycle.

All patients will receive vitamin therapy on a regimen of folic acid by mouth (PO) once a day (QD) starting at least 7 days prior to enrollment and must receive 1 mg intramuscular (IM) vitamin B12 within 10 weeks of enrollment. Once the patient is enrolled, the dosing of vitamin supplementation will consist of vitamin B12 1 mg IM q 8 10 weeks, and folic acid PO QD.

All patients will be followed for safety until 35 (± 5) days after the last dose of pralatrexate, or until all treatment-related adverse events (AEs) have resolved or returned to baseline/Grade 1, whichever is longer, or until it is determined that the outcome will not change with further follow up.

Inclusion Criteria:

1. Histologically confirmed TCC (> 50% TCC in tumor) of the urinary bladder. Fine needle aspirate will not be accepted.
2. Relapsed or progressed after at least 6 months of treatment with no more than 1 platinum- and/or methotrexate-based systemic chemotherapy regimen for metastatic disease. Patients treated neoadjuvantly or adjuvantly must have relapsed within 6 months of receiving no more than 1 previous platinum-based chemotherapy regimen. Patient has recovered from the toxic effects of prior therapy. Previous intravesical therapy is allowed. Prior surgical resection is allowed, as long as the patient has recovered.
3. Measurable disease outside a previously irradiated region, per Response Evaluation Criteria in Solid Tumors (RECIST).
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. ≥ 18 years of age.
6. Adequate hematologic, hepatic, and renal function as defined by: hemoglobin (Hgb) ≥ 10 g/dL (≥ 100 g/L); white blood cell (WBC) count ≥ 2500 cells/mm3 (≥ 2.5 x 109 cells/L); absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (≥ 1.5 x 109 cells/L); platelet count ≥ 100,000/mm3; calculated creatinine clearance (CrCl) of ≥ 50 mL/min; total bilirubin ≤ 1.5 x the upper limit of normal (ULN); and aspartate aminotransferase (AST, serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT, serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x ULN.
7. The patient has been on a regimen of 1 1.25 mg PO QD of folic acid for at least 7 days prior to enrollment and has received 1 mg IM of vitamin B12 within 10 weeks of enrollment.
8. Women of childbearing potential have a negative serum pregnancy test within 14 days prior to enrollment and must agree to practice a medically acceptable and effective contraceptive regimen from enrollment until at least 30 days after the last administration of pralatrexate. Patients who are postmenopausal for at least 1 year (> 12 months since last menses) or are surgically sterilized do not require this test.
9. Men who are not surgically sterile and whose partner is of childbearing potential must be practicing a medically safe and effective contraceptive regimen from the time of pralatrexate initiation, and agree to continue practicing until at least 90 days after the last administration of pralatrexate.
10. Accessible for repeat dosing and follow up.
11. Given written informed consent (IC).

Exclusion Criteria:

1. Active concurrent primary malignancy or prior malignancies occurring within 5 years (except non-melanoma skin cancer, in situ carcinoma of the cervix, or occult, indolent carcinoma of the prostate [undetectable prostate-specific antigen, Gleason score ≤ 7, no seminal vesicle invasion, and no extraprostatic extension]). If there is a history of prior malignancies other than those exceptions listed above, the patient must be disease free for ≥ 5 years. Patients with other prior malignancies less than 5 years before study entry may still be enrolled if they have received treatment resulting in complete resolution of the cancer and currently have no clinical, radiologic, or laboratory evidence of active or recurrent disease. In the case of a single extrapelvic metastatic site, irrespective of the patient having a history of previous malignancy, a biopsy proof of the metastatic diseased organ will be necessary.
2. More than 1 previous regimen for either neoadjuvant/adjuvant or advanced disease (except simultaneous chemoradiotherapy).
3. Evidence of clinically significant active thirdspace phenomenon; ie, peripheral edema (≥ + 2), active pleural effusion, or ascites.
4. Use of any investigational drugs, biologics, or devices within 28 days prior to study enrollment.
5. Previous exposure to other antifolates (eg, methotrexate, pemetrexed [Alimta]). Previous methotrexate is allowed, only if it was part of a methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (M-VAC) or methotrexate, cisplatin, and vinblastine (MCV) regimen and provided that 6 months has elapsed since treatment with M-VAC or MCV.
6. Previous exposure to pralatrexate.
7. Women who are pregnant or breastfeeding.
8. Congestive Heart Failure Class III/IV according to New York Heart Association (NYHA) Functional Classification.
9. Uncontrolled hypertension.
10. Human immunodeficiency virus (HIV)-positive diagnosis with a CD4 count of < 100 mm3 or detectable viral load within the past 3 months, and is receiving combination anti-retroviral therapy.
11. Central nervous system (CNS) metastatic disease.
12. Major surgery within 2 weeks of study enrollment.
13. Receipt of any conventional systemic chemotherapy or RT within 4 weeks (6 weeks for nitrosoureas, mitomycin C) prior to study enrollment.
14. Active infection or any serious underlying medical condition, which would impair the ability of the patient to receive protocol treatment.
15. Dementia or significantly altered mental status that would prohibit the understanding and giving of IC or limit study compliance.