Phase II Pazopanib in Combination With Weekly Paclitaxel in Refractory Urothelial Cancer

Study Overview
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Brief Summary
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We will combine an oral investigational vascular endothelial growth factor (VEGF inhibitor) called pazopanib which is being studied in kidney cancer will be combined with standard chemotherapy called taxol in patients with relapsed recurrent urothelial cancer.

Detailed Description
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Based on the results from the Phase 1 study of pazopanib combined with paclitaxel and the activity of paclitaxel in urothelial cancer, testing this regimen in a disease where there is an unmet need appears appropriate.

Official Title
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A Phase II Study of Pazopanib in Combination With Weekly Paclitaxel in Refractory Urothelial Cancer

Conditions
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Bladder Cancer, Bladder (Urothelial, Transitional Cell) Cancer, Bladder (Urothelial, Transitional Cell) Cancer Superficial (Non-Invasive), Bladder (Urothelial, Transitional Cell) Cancer Resectable (Pre-Cystectomy), Bladder (Urothelial, Transitional Cell) Cancer Metastatic or Unresectable

Intervention / Treatment
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* Drug: Pazopanib (GW786034)
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed transitional cell carcinoma (TCC) of the urothelium (bladder, renal pelvis, ureter, or urethra). Mixed histology is allowed as long as the predominant histology is TCC First recurrence after treatment with a maximum of two chemotherapeutic regimens. Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow up. Procedures conducted as part of the subject's routine clinical management (eg, blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol. Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Measurable disease criteria by RECIST criteria Adequate organ system function as defined below Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L Hemoglobin ≥ 9 g/dL Platelets ≥ 100 X 10^9/L Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.2 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 x ULN aspartate aminotransferase (AST) and Alanine Aminotransferase (ALT)≤ 2.5 x ULN Serum creatinine ≤ 1.8 mg/dL Urine Protein to Creatinine Ratio (UPC) < 1 A female is eligible to enter and participate in this study if she is of non-childbearing potential (ie, physiologically incapable of becoming pregnant). This includes any female who has had: A hysterectomy A bilateral oophorectomy (ovariectomy) A bilateral tubal ligation Menopause Childbearing potential females must have a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agree to use adequate contraception. Adequate acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow: An intrauterine device with a documented failure rate of less than 1% per year. Vasectomized partner who is sterile prior to the female subject's entry and is the sole sexual partner for that female. Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product. Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm with spermicide). Exclusion Criteria: History of other malignancies within 5 years prior to Day 1 except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal cell carcinoma, squamous-cell carcinoma of the skin, carcinoma in situ of the cervix, early-stage bladder cancer, or low-grade endometrial cancer Malignancies that have undergone a putative surgical cure (ie, localized prostate cancer post-prostatectomy) within 5 years prior to Day 1 may be discussed with the Medical Monitor 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. Clinically significant gastrointestinal abnormalities that may increase the risk for GI bleeding Clinically significant gastrointestinal abnormalities that may affect absorption of the investigational product Presence of uncontrolled infection. Prolongation of corrected QT interval (QTc) > 480 milliseconds. On antiarrhythmics or medications known to prolong QT interval 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 by-pass 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 ≥ 90mm Hg]. History of cerebrovascular accident, hemoptysis, cerebral hemorrhage, clinically significant GI bleed, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture Evidence of active bleeding or bleeding diathesis. 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 procedures. Patients on strong CYP3A4 inhibitors Uncorrected abnormal electrolytes: K, Mg and Ca Prior treatment with taxane chemotherapy 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 chemotherapy, 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

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: pazopanib + paclitaxel<br>Cycle of 28 days. Pazopanib: 800mg daily Cycle of 28 days Paclitaxel: 80mg/m2 on days 1,8 and 15 | Drug: Pazopanib (GW786034)<br>* Cycle of 28 days. Pazopanib: 800mg/day<br>* Other names: GW786034;Drug: Paclitaxel<br>* Cycle of 28 days Paclitaxel: 80mg/m2 days 1,8 and 15<br>* Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response | The tumor response rate was assessed per the Response Evaluation Criteria In Solid Tumors (RECIST). RECIST criteria are a set of published rules that define when cancer patients improve (respond); stay the same (stable); or worsen (progression) during treatments. RECIST criteria offer a simplified and conservative extraction of imaging data suitable for wide application in clinical trials. The criteria presume that linear measures are an adequate substitute for 2-dimensional (2D) methods and includes 4 response categories: Complete response (CR) = Disappearance of all target lesions Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions Stable disease (SD) = Small changes that do not meet above criteria Objective tumor response means those with response better than stable disease, ie, complete response (CR) + partial response (PR). | Every 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) |  | 4 years | 
| Overall Response Rate | The tumor response rate was assessed per the Response Evaluation Criteria In Solid Tumors (RECIST). RECIST criteria are a set of published rules that define when cancer patients improve (respond); stay the same (stable); or worsen (progression) during treatments. RECIST criteria offer a simplified and conservative extraction of imaging data suitable for wide application in clinical trials. The criteria presume that linear measures are an adequate substitute for 2-dimensional (2D) methods and includes 4 response categories: Complete response (CR) = Disappearance of all target lesions Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions Stable disease (SD) = Small changes that do not meet above criteria Tumor response rate by each response criteria. | 4 years | 
| Overall Survival | Overall survival is reported as the median survival of the evaluable subjects (ie, completed 2 cycles of treatment). | 4 years | 
| Median Overall Survival (OS) by Bellmunt Score | Comparison between the participant's baseline Bellmunt prognostic risk factor score and survival rates. The Bellmunt prognostic risk factor score is a tool that is often used to predict treatment outcomes before initiating a secondline treatment regimen. The risk factors used to calculate the Bellmunt score include: Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 Presence of liver metastases Presence of visceral involvement (defined as liver, lung, bone or any non-lymph node) Lymph node-only involvement Hemoglobin concentration < 10 g/dL The score is calculated based on the presence of 0; 1; 2; or 3 of the above prognostic factors. This outcome reports median overall survival based on whether the participant had 0; 1; 2; or 3 prognostic factors. | 4 years |