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

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
• •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).