Vorinostat in Treating Patients With Locally Recurrent or Metastatic Cancer of the Urothelium

Study Overview
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Brief Summary
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Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase II trial is studying how well vorinostat works in treating patients with locally recurrent or metastatic cancer of the urothelium.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine response rate measured by RECIST criteria for SAHA in patients with recurrent or metastatic transitional cell carcinoma of the urothelium. SECONDARY OBJECTIVES: I. To determine the time to progression and overall survival for SAHA in patients with recurrent or metastatic transitional cell carcinoma of the urothelium. II. To provide data on safety and toxicity of SAHA in patients with recurrent or metastatic transitional cell carcinoma of the urothelium. III. To obtain preliminary data on molecular correlates in tissue, oral mucosa and blood to determine feasibility and clinical efficacy. OUTLINE: This is a multicenter study. Patients receive oral vorinostat (SAHA) twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and buccal mucosa collection and tumor biopsies (if accessible) at baseline and periodically during study for correlative studies. Samples are examined by gene expression profiling and immunohistochemistry. After completion of study treatment, patients are followed for up to 26 weeks. PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.

Official Title
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Phase II Study of Oral Suberoylanilide Hydroxamic Acid (SAHA) in Recurrent or Metastatic Transitional Cell Carcinoma of the Urothelium

Conditions
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Localized Transitional Cell Cancer of the Renal Pelvis and Ureter, Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter, Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter, Regional Transitional Cell Cancer of the Renal Pelvis and Ureter, Transitional Cell Carcinoma of the Bladder

Intervention / Treatment
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* Drug: vorinostat
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a pathological diagnosis of transitional cell carcinoma of the bladder or urothelium with less than 25% component of other cell types such as small cell, neuroendocrine or squamous cell carcinoma; archival tumor tissue must be available for classification and correlates as described in this protocol or otherwise the patient must be willing to undergo biopsy prior to trial entry Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan; patients with boney metastases are allowed to participate in the study provided they also have non-osseous disease that is measurable Patients must have recurred or progressed on or subsequent to platinum-based chemotherapy in the adjuvant or advanced setting; patients treated with a second line of chemotherapy may be included provided more than six months elapsed from the completion of the first line of chemotherapy to the start of the second; patients may have had any number of prior intravesical therapies for superficial bladder cancer; patients may also have had one experimental biologic therapy for their metastatic urothelial cancer provided this was not an agent known to act through histone deacetylation or demethylation; these compounds include sodium butyrate, trichostatin A (TSA), trapoxin (TPX), MS-27-275 and depsipeptide Life expectancy of greater than 3 months ECOG performance status =< 2 (Karnofsky >= 60%) Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin within normal institutional limits AST (SGOT)/ALT (SGPT) =< 2.5 x institutional upper limit of normal unless there are liver metastases in which case AST/ALT must be =< 5 x the upper limits of institutional normal Creatinine =< 1.5 times normal institutional limits OR creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine levels above 1.5 times institutional normal Eligibility of patients receiving any medications or substances known to effect or with the potential to effect the activity or pharmacokinetics of SAHA will be determined following review 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; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Patients may not be receiving any other investigational agents Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events History of allergic reactions attributed to compounds of similar chemical or biologic composition to SAHA; these compounds include sodium butyrate, trichostatin A (TSA), trapoxin (TPX), MS-27-275 and depsipeptide Prior treatment with more than 2 cytotoxic chemotherapy regimens for urothelial transitional cell cancer Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this stud; breastfeeding should be discontinued if the mother is treated with SAHA HIV-positive patients receiving combination antiretroviral therapy are ineligible Patients should not have taken valproic acid for at least two weeks prior to study entry

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 (vorinostat)<br>Patients receive oral vorinostat (SAHA) twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;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 |
| --- | --- | --- |
| Objective Tumor Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Response assessed after every 2 cycles (6 weeks) up to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Will be estimated using the product-limit method of Kaplan and Meier. | Up to 26 weeks | 
| Progression-free Survial | Will be estimated using the product-limit method of Kaplan and Meier. Progression defined using RECIST v1.0 criteria, at least a 20% increase in the sum of the longest diameter of target lesions, or the appearance of one or more new lesions. | assessed up to 26 weeks |