Sunitinib Malate in Treating Patients With Recurrent Transitional Cell Bladder Cancer

Study Overview
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Brief Summary
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RATIONALE: Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well sunitinib malate works in treating patients with recurrent transitional cell bladder cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the clinical efficacy of oral sunitinib (Sutent) given continuously for a maximum of 12 weeks, with respect to complete response rates at 12 months after completion of treatment in patients with high-risk superficial bladder cancer who have failed previous intravesical BCG. SECONDARY OBJECTIVES: I. To assess the impact of sunitinib treatment in recurrence-free survival, progression-free survival, and overall survival in patients with high-risk superficial TCC of the bladder who have failed previous intravesical BCG. II. To evaluate the safety and tolerability of sunitinib (Sutent) administered in patients with high-risk superficial TCC of the bladder who have failed previous intravesical BCG. TERTIARY OBJECTIVES: I. To assess pre-treatment tissue baseline angiogenic markers and to evaluate the magnitude of the difference among these variables with post-treatment tumor tissue after treatment with sunitinib (Sutent). II. To evaluate the effects of Sunitinib (Sutent) on immunosuppressive regulatory T cells (Tregs). III. To determine the presence of circulating tumor cells in superficial BCG-refractory TCC patients. OUTLINE: Patients receive oral sunitinib malate once daily on days 1-28. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Official Title
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Phase II Single Arm, Open Label, Single Institution Study of Continuous Sunitinib (Sutent) in Patients With High-Risk (BCG-Refractory) Superficial Transitional Cell Carcinoma (TCC) of the Bladder

Conditions
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Transitional Cell Carcinoma of the Bladder, Recurrent Bladder Cancer

Intervention / Treatment
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* Drug: sunitinib malate
* Other: immunohistochemistry staining method
* Other: TdT-mediated dUTP nick end labeling assay
* Other: light microscopy
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Patients must have clinically and histologically proven, recurrent superficial transitional cell carcinoma of the bladder after treatment with BCG therapy Patients could have received previous any INTRAVESICAL therapy including BCG and/or IFN and/or chemotherapy up to 3 years prior to registration Patients biopsy specimen should be available for review ECOG PS 0-1 (Karnofsky greater than 70%) Absolute neutrophil count >= 1,000/mcL Platelets >= 100,000/mcL Hemoglobin >= 8.5 g/dl Total bilirubin =< 1.5 X institutional upper limit of normal AST(SGOT)/ALT(SGPT) =< 3.5 X institutional upper limit of normal Alkaline phosphatase =< 2.5 ULN ( =< 10 x ULN in presence of bone metastasis) Serum calcium of =< 12 mg/dl Creatinine =< 1.5 X institutional upper limit of normal INR =< 1.5, except for subjects receiving warfarin therapy Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of Sunitinib (Sutent) will be determined following review of their case by the Principal Investigator Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; sexually active patients must continue to use contraception for three months after completion of study therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately All patients must be informed of the investigational nature of this study and must provide written informed consent in accordance with institutional and federal guidelines Exclusion Prior systemic chemotherapy for bladder cancer; all other systemic chemotherapy must have been completed at least 3 years prior to enrollment Prior treatment with any other anti-angiogenic therapy (including immunomodulatory agents such as thalidomide and lenalidomide, and anti-VEGF therapy with agents such as bevacizumab (Bevacizumab Avastin, Sunitinib (Sutent) and Sorafenib (Nexavar) Prior major surgery (not TURBT/Cystoscopy), radiation therapy, or systemic therapy within 4 weeks of starting the study treatment NCI CTCAE grade 3 hemorrhage within 4 weeks of starting study treatment Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism Ongoing cardiac dysrhythmias of NCI CTCAE grade >= 2, or prolongation of the QTc interval to > 450 msec for males or > 470 msec for females (Atrial Fibrillation is allowed provided patients are rated controlled) Hypertension that cannot be controlled by medications Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) - related illness or infectious hepatitis type A, B or C Disease-free of prior malignancies for >= 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment Pregnancy or breastfeeding (Female patients must be surgically sterile or postmenopausal, or must agree to use effective contraception during the period of therapy; all female patients with reproductive potential must have a negative pregnancy test [serum or urine] prior to enrollment) Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy (The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate)

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: Arm I<br>Patients receive oral sunitinib malate once daily on days 1-28. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. | Drug: sunitinib malate<br>* Given orally<br>* Other names: Sutent;Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Other: TdT-mediated dUTP nick end labeling assay<br>* Correlative studies<br>* Other names: TUNEL assay;Other: light microscopy<br>* Correlative studies<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Number of patients with complete response defined as negative cystoscopy with negative biopsy and no evidence of cancer on urine cytology 12 months after treatment with sunitinib. | At 12 months after completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free Survival | Time from registration (up to 28 days prior to treatment) to the first documentation of recurrence assessed up to 12 months after completion of treatment (up to 12 weeks). Time period can be up to 16 months from time of registration. | at 12 months after completion of treatment | 
| Progression-free Survival | Number of patients last known to be alive and not to have progressed are censored at the last day of contact. Progression is defined as: Biopsy proven muscle invasive disease ≥ Stage T2 or death due to any cause. | at 12 months after completion of treatment | 
| Overall Survival | Number of patients still alive from date of registration to date of death due to any cause. | at 12 months after completion of treatment | 
| Toxicity Assessed, Graded, and Tabulated Using CTCAE Version 3.0 | Number of participants that experienced adverse events. | at 12 months after completion of treatment |