Gemcitabine and Pazopanib in Chemotherapy Naïve Patients With Advanced/Metastatic Urothelial Carcinoma Ineligible for Cisplatin-based Chemotherapy

Inclusion Criteria: * Age ≥ 18 years * Histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis by MSKCC pathology review * Measurable disease as determined by RECIST v1.1 on initial pretreatment staging CT scan of the chest, abdomen, and pelvis (or MRI if clinically appropriate). (Note: A chest x-ray may be performed as an alternative to a CT scan of the chest.) * Ineligible for cisplatin based on one or more of the following: * Calculated creatinine clearance of \< 60 mL/min (but ≥ 30 mL/min) * Karnofsky Performance Status (KPS) 60-70% (ECOG PS 2) * Grade 2 ≥ hearing loss * Grade 2 ≥ peripheral neuropathy * Karnofsky Performance Status ≥ 60% * 10 unstained slides or paraffin embedded tissue block obtained from pretreatment tumor specimens for immunohistochemistry. (Note: One paraffin block or 10 freshly-prepared unstained slides from the most representative single paraffin embedded tumor tissue block should be submitted. Slides from the primary tumor are preferred. If both the primary and metastatic tumor blocks are available, 10 slides from each of the sites should be submitted. If tissue from the primary tumor is not available, a paraffin block or unstained slides from a metastatic site are acceptable. Fine needle aspirates (FNAs) have insufficient tumor tissue and are not permitted.) * Adequate organ system function as defined: * Absolute neutrophil count (ANC) ≥1.5 X 109/L * Hemoglobin ≥9 g/dL (5.6 mmol/L) (Note: Subjects may not have had a transfusion within 7 days of screening assessment.) * Platelets ≥100 X 109/L * Prothrombin time (PT) or international normalized ratio (INR) ≤1.2 X ULN (Note: Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation.) * Activated partial thromboplastin time (aPTT) ≤1.2 X ULN * Total bilirubin ≤1.5 X ULN * Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 X ULN (Note: Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted.) * Calculated creatinine clearance (ClCR) ≥30 mL/min using the CKD-EPI equation: eGFR = 141 x min(Scr/k, 1)a x max(Scr/k, 1)-1.209 x 0.993 Age x 1.018 \[if female\] x 1.159 \[if black\] Scr is serum creatinine, k is 0.7 for females and 0.9 for males, a is - 0.329 for females and -0.411 for males, min indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1 * Urine Protein to Creatinine Ratio (UPC)d \<1 (Note: If UPC ≥1, then a 24- hour urine protein must be assessed. Subjects must have a 24-hour urine protein value \<1 g to be eligible.) Exclusion Criteria: * Prior treatment with systemic chemotherapy (prior intravesical therapy is permitted) * Prior malignancy (Note: Subjects who have had another malignancy and have been disease-free for 5 years subjects with a history of completely resected non-melanomatous skin carcinoma, subjects with successfully treated in situ carcinoma, or subjects who have had adenocarcinoma of the prostate that has been definitively treated with a post-treatment PSA that is non-detectable are eligible.) * History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 months prior to first dose of study drug. Screening with CNS imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) is required only if clinically indicated or if the subject has a history of CNS metastases. * Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to: * Active peptic ulcer disease * Known intraluminal metastatic lesion/s with risk of bleeding * Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: * Malabsorption syndrome * Major resection of the stomach or small bowel * Active liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis * Presence of uncontrolled infection Corrected QT interval (QTc) \> 480 msecs using Bazett's formula o If QTc interval is \> 480 msecs, then 2 additional ECGs should be obtained over a brief period of time (e.g., within approximately 15-20 minutes) to confirm the abnormality. The average QTc interval will be determined from the 3 ECG tracings by manual evaluation and will be used to determine if the subject will be excluded from the study. If the average QTc interval is \>480 msec, then the subject is not eligible to participate in the study Previous history of QTc prolongation as a result of other medication that required discontinuation of that medication * Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age * Use of any concomitant medication (during treatment with pazopanib or within 14 days of starting treatment) that are high risk for QTc prolongation or may induce Torsades de Pointes. * History of any one or more of the following cardiovascular conditions within the past 6 months: * Cardiac angioplasty or stenting * Myocardial infarction Unstable angina * Coronary artery bypass graft surgery * Symptomatic peripheral vascular disease * Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) * Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg\] (Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. At least 24 hours after initiation or adjustment of antihypertensive medication (s), BP must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from each BP assessment must be \<140/90 mmHg in order for a subject to be eligible for the study.) * History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. (Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.) * Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major). * Evidence of active bleeding or bleeding diathesis. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels * Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug. * Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures. * Unable or unwilling to discontinue use of prohibited medications listed in (Concomitant Therapy) for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study * Treatment with any of the following anti-cancer therapies: * Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib OR * Immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment * Any ongoing toxicity from prior anti-cancer therapy that is \>Grade 1 and/or that is progressing in severity * Women who are pregnant or breast feeding (Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.) * Adults of child-bearing potential not employing an effective method of birth control for two weeks prior to study start and 21 days after the last dose. All women of child-bearing potential must have a negative serum pregnancy test. Women of child-bearing potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy (ovariectomy), or bilateral tubal ligation OR have not experienced total cessation of menses for ≥ 1 year and are older than 45 years in age, In questionable cases, the patient must have a follicle stimulating hormone (FSH) value \>40 mIU/mL and an estradiol value \< 40pg/mL (\<140 pmol/L). Effective methods of birth control are defined in section 9.9 (Contraception Requirements).