Pazopanib in Treating Patients With Metastatic Urothelial Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Safety and Efficacy Study With the VEGF Receptor Tyrosine Kinase Inhibitor GW786034 in Patients With Metastatic Urothelial Cancer

Conditions
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Distal Urethral Cancer, Proximal Urethral Cancer, Recurrent Bladder Cancer, Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter, Recurrent Urethral Cancer, Stage IV Bladder Cancer, Transitional Cell Carcinoma of the Bladder, Urethral Cancer Associated With Invasive Bladder Cancer

Intervention / Treatment
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* Drug: pazopanib hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy)<br>Patients receive 800 mg oral pazopanib hydrochloride once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: pazopanib hydrochloride<br>* 800 mg Given orally<br>* Other names: Votrient;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Tumor Response (Complete [CR] or Partial Response [PR] by Response Evaluation Criteria in Solid Tumors [RECIST]) | Tumor response is defined as the total number of eligible patients whose disease has a complete or partial response to GW786034 according to the RECIST criteria. Per RECIST v1.0 criteria: A Complete Response (CR) requires the disappearance of all target lesions. A Partial Response (PR) requires >=30% decrease in the sum of the longest diameter of target lesions from baseline measurement. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for response. | Participants will be evaluated every 8 weeks during treatment and up to 1 year after completion of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | The maximum grade for each adverse event considered to be at least possibly related to treatment will be recorded. Frequency tables will be constructed. | Every 4 weeks during treatment (maximum duration was 44 weeks) | 
| Confirmed Tumor Response (CR and PR) | Tumor response is defined as the total number of eligible patients whose disease has a complete or partial response to GW786034 according to the RECIST criteria. A confirmed response is defined as a CR or PR and is documented on 2 consecutive evaluations. | Documented on 2 consecutive evaluations 8 weeks apart from the start of the treatment until disease progression/recurrence, assessed up to 1 year | 
| Duration of Response | The distribution of response durations will be estimated using the Kaplan-Meier method. | From the time an objective response is first noted to be either a CR or PR to the date progression is documented, assessed up to 1 year | 
| Time to Disease Progression | The distribution of progression-free survival times will be estimated using the Kaplan-Meier method. | Every 3 months from registration until progressive disease (PD), assessed up to 2 years after registration | 
| Survival Time | The distribution of survival times will be estimated using the Kaplan-Meier method. | Time from registration until death due to any cause, assessed every 6 months after PD for up to 2 years after registration |