Sunitinib in Treating Patients With Locally Advanced Bladder Cancer

Study Overview
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Brief Summary
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RATIONALE: Sunitinib 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. Giving sunitinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying the side effects and how well sunitinib works in treating patients with locally advanced bladder cancer.

Detailed Description
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OBJECTIVES: Primary To determine the pathologic complete response rate of sunitinib malate in patients with muscle-invasive locally advanced transitional cell carcinoma (TCC) of the bladder. To evaluate the safety and tolerability of sunitinib malate administered prior to radical cystectomy, including surgical outcome and surgical complications. Secondary To determine the clinical effects of sunitinib malate administered prior to radical cystectomy and bilateral lymph node dissection, including overall response rate using RECIST defined criteria, cytology, and histologic appearance of surgical specimen as well as time to progression. Tertiary 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 neoadjuvant sunitinib malate. To evaluate the effects of sunitinib malate on immunosuppressive regulatory T cells. OUTLINE: Patients receive oral sunitinib malate once daily in weeks 1-4 (1 course). Patients undergo restaging within 1 week prior to surgery and then undergo radical cystectomy and bilateral lymph node dissection on day 42. Patients achieving a complete pathologic response at the time of surgery may receive 6 more courses of adjuvant sunitinib malate beginning 28 days after surgery at the discretion of the treating physician. Patients found to have high-risk features (i.e. pT3 or greater tumor and evidence of disease in any of the lymph nodes resected) are offered standard adjuvant systemic chemotherapy at the discretion of the treating physician. Tumor tissue from pretreatment biopsy and radical cystectomy will be tested for VEGFR-1, VEGFR-2 and PDGF-R expression by IHC. Samples are also analyzed for quantification of cell proliferation and apoptosis and immunosuppressive regulatory T cells (T-reg) and T-reg functions. After completion of study treatment, patients are followed at 28 days after surgery.

Official Title
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Phase II Single Arm, Open Label, Single Institution Study of Neoadjuvant Sunitinib (SUTENT) in Patients With Muscle-Invasive Locally Advanced Transitional Cell Carcinoma of the Bladder

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: sunitinib malate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Inclusion criteria: Histological confirmed transitional cell carcinoma (TCC) of the bladder Patients with mixed tumors (i.e., tumors containing elements of squamous cell or adenocarcinoma) are eligible Patients with pure non-transitional cell carcinomas are not eligible Meets 1 of the following staging criteria: Tumors ≥ cT2 Patients with cT2 lesions must have either a bulky or fixed lesion at the time of physical examination and/or scans Any cT stage with nodal-positive disease (documented by scans) Patients with (+) N1-N3 disease are eligible Candidate for radical cystectomy in ≥ 8 weeks while neoadjuvant sunitinib malate is administered Exclusion criteria: Any evidence of distant metastasis (excluding pelvic or retroperitoneal lymph nodes) PATIENT CHARACTERISTICS: Inclusion criteria: ECOG performance status (PS) 0-1 (Karnofsky PS greater than 70%) Absolute neutrophil count ≥ 1,500/mcL Platelet count ≥ 100,000/mcL Hemoglobin ≥ 8.5 g/dL Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN) AST and ALT ≤ 3.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN (≤ 10 times ULN in presence of bone metastasis) Serum calcium ≤ 12 mg/dL Creatinine ≤ 1.5 times ULN INR ≤ 1.5 (except for patients receiving warfarin therapy) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study treatment Disease-free of prior malignancies for ≥ 5 years except for currently treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix Exclusion criteria: NCI CTCAE grade 3 hemorrhage within 4 weeks of starting study treatment Any of the following within 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 Pulmonary embolism Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥ 2, atrial fibrillation of any grade, or prolongation of the QTc interval to > 450 msec for males or > 470 msec for females Hypertension that cannot be controlled by medications Known HIV or AIDS-related illness Infectious hepatitis type A, B, or C 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 PRIOR CONCURRENT THERAPY: Inclusion criteria: Other systemic chemotherapy must have been completed at least 5 years prior to enrollment No prior systemic chemotherapy for bladder cancer No other approved or investigational anticancer treatment will be permitted during the study period, including chemotherapy, biological response modifiers, hormone therapy, surgery, palliative radiotherapy, or immunotherapy No other investigational drug may be used during treatment on this protocol No concurrent participation in another clinical trial Exclusion criteria: Prior intravesical chemotherapy or immunotherapy Prior treatment with any other antiangiogenic therapy (including immunomodulatory agents such as thalidomide and lenalidomide and anti-VEGF therapy with agents such as bevacizumab, sunitinib malate, and sorafenib tosylate) Prior surgery, radiotherapy, or systemic therapy within 4 weeks of starting the study treatment

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: sunitinib malate<br>Drug | Drug: sunitinib malate<br>* 50mg PO daily 4 weeks on -2 weeks off<br>* Other names: Drug;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate of Sunitinib | Number of participants who at the time of cystectomy, to have no evidence of tumor grossly and microscopically on routine Hematoxylin and Eosin stain (H&E) (pathologic complete response or P0) will be defined as responders. All cases will be defined as responders (P0) or non-responders based on the presence of residual tumor. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression (PD): At least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD since the treatment started. | at 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Treatment to Surgical Complication and Morbidity | Determine if surgical morbidity was increased from time of last dose to time of surgery is defined as the number of subjects with increase non-ileus related morbidity due to treatment drug during the 2 week rest period. | following surgery at 6 weeks | 
| Time to Progression | Time to progression will be measured as the time from when the patient started treatment to the time the patient is first recorded as having disease progression or the date of death if the patient dies due to causes other than disease progression. | at 4 weeks post-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transitional cell carcinoma of the bladder, stage II bladder cancer, stage III bladder cancer, stage IV bladder cancer