Pazopanib in Treating Patients With Metastatic Urothelial Cancer
Pazopanib in Treating Patients With Metastatic Urothelial Cancer
This phase II trial is studying the side effects and how well pazopanib works in treating
 patients with metastatic urothelial cancer. Pazopanib may stop the growth of tumor cells by
 blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
PRIMARY OBJECTIVES:

 I. Assess the anti tumor activity and toxicity profile of pazopanib hydrochloride in patients
 with metastatic urothelial cancer.

 SECONDARY OBJECTIVES:

 I. Evaluate the pharmacokinetics of pazopanib hydrochloride in these patients. II. Evaluate
 pre- and post-treatment changes in circulating endothelial cells, monocytes and platelets,
 and angiogenesis-related factors in these patients.

 OUTLINE: This is a multicenter study. Patients receive oral pazopanib hydrochloride once
 daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or
 unacceptable toxicity.

 Patients undergo blood collection periodically for correlative studies and pharmacological
 studies. Samples are analyzed for vascular endothelial growth factor (VEGF) and soluble VEGF
 receptor II concentration via ELISA. Circulating endothelial cells are also measured.

 After completion of study treatment, patients are followed for 1 year.
Inclusion Criteria:

 -  Histologically or cytologically confirmed transitional cell cancer of the urothelium
 or bladder

 -  Metastatic disease

 -  Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 2.0 cm by
 conventional techniques OR ≥ 1.0 cm by spiral CT scan

 -  No known brain metastases

 -  ECOG performance status 0-2

 -  Life expectancy ≥ 12 weeks

 -  Platelet count ≥ 100,000/mm^3

 -  WBC ≥ 3,000/mm^3

 -  Absolute neutrophil count ≥ 1,500/mm^3

 -  Bilirubin normal

 -  AST and ALT ≤ 2.5 times upper limit of normal (ULN)

 -  Creatinine normal OR creatinine clearance ≥ 60 mL/min

 -  PT/INR/PTT ≤ 1.2 times ULN

 -  No proteinuria > 1+ on two consecutive dipsticks measured ≥ 1 week apart

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  No history of allergic reactions attributed to compounds of similar chemical or
 biological composition to pazopanib hydrochloride or other agents used in the study

 -  No condition that impairs the ability to swallow and retain pazopanib hydrochloride
 tablets, including any of the following:

 -  Gastrointestinal tract disease resulting in an inability to take oral medication

 -  Requirement for IV alimentation

 -  Prior surgical procedures affecting absorption

 -  Active peptic ulcer disease

 -  No uncontrolled illness that would limit compliance with study therapy including, but
 not limited to, any of the following:

 -  Ongoing or active infection

 -  Psychiatric illness or social situations

 -  No QTc prolongation (defined as a QTc interval ≥ 480 msecs) or other significant ECG
 abnormalities (e.g., frequent ventricular ectopy, evidence of ongoing myocardial
 ischemia)

 -  No other conditions, including any of the following:

 -  Serious or non-healing wound, ulcer, or bone fracture

 -  Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
 within the past 28 days

 -  Cerebrovascular accident within the past 6 months

 -  Myocardial infarction, cardiac arrhythmia, or admission for unstable angina
 within the past 12 weeks

 -  Venous thrombosis within the past 12 weeks

 -  New York Heart Association (NYHA) class III or IV heart failure

 -  Asymptomatic NYHA class II heart failure on treatment allowed

 -  No other active second malignancy other than non-melanoma skin cancer

 -  Patients are not considered to have an active malignancy if they have completed
 anti-cancer therapy and are considered by their physician to be ≤ 30% risk of
 relapse

 -  At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
 and recovered

 -  At least 4 weeks since prior radiotherapy

 -  Prior palliative radiotherapy to metastatic lesions allowed provided there is ≥ 1
 measurable and/or evaluable lesion(s) that has not been irradiated

 -  At least 4 weeks since prior surgery

 -  One prior chemotherapy regimen for metastatic urothelial or bladder cancer

 -  More than 12 weeks since prior cardiac angioplasty or stenting

 -  Prior adjuvant or neoadjuvant therapy allowed

 -  No prior experimental treatment for metastatic disease

 -  No other prior or concurrent investigational agents

 -  No concurrent combination antiretroviral therapy for HIV-positive patients

 -  No concurrent CYP2C9 substrates, including any of the following:

 -  Anticoagulants (e.g., warfarin [therapeutic doses only])

 -  Low molecular weight heparin and prophylactic low-dose warfarin (≤ 2 mg
 daily) allowed

 -  Oral hypoglycemics (e.g., glipizide, glyburide, tolbutamide, glimepiride, or
 nateglinide)

 -  Ergot derivatives (e.g., dihydroergotamine, ergonovine, ergotamine, or
 methylergonovine)

 -  Antipsychotics (e.g., pimozide or clozapine)

 -  Erectile dysfunction agents (e.g., sildenafil, tadalafil, or vardenafil)

 -  Antiarrhythmics (e.g., bepridil, flecainide, lidocaine, mexiletine, amiodarone,
 quinidine, or propafenone)

 -  Immune modulators (e.g., cyclosporine, tacrolimus, or sirolimus)

 -  Miscellaneous drugs (e.g., theophylline, quetiapine, risperidone, tacrine, or
 atomoxetine)

 -  No other concurrent anticancer agents or therapies

 -  No concurrent medications that are associated with a risk of QTc prolongation and/or
 Torsades de Pointes