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

Condition(s) targeted: Bladder Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Urethral Cancer

Intervention: vorinostat (Drug); gene expression profiling (Procedure); immunohistochemistry staining method (Procedure)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: California Cancer Consortium

Official(s) and/or principal investigator(s):
David I. Quinn, MD, Study Chair, Affiliation: Norris Comprehensive Cancer Center

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying how well vorinostat works in treating patients with locally recurrent or metastatic cancer of the urothelium.

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

Study design: Treatment, Open Label

Primary outcome: Objective tumor response rate as measured by RECIST criteria

Secondary outcome:

Time to progression

Overall survival

Toxicity profile as measured by NCI CTCAE v3.0 at the beginning of each treatment course

Feasibility and clinical efficacy of vorinostat (SAHA) using molecular correlates in tissue, oral mucosa, and blood

Detailed description: OBJECTIVES:

Primary

- Determine response rate (as measured by RECIST criteria) in patients with locally

recurrent or metastatic transitional cell carcinoma of the urothelium treated with vorinostat (SAHA).

Secondary

- Determine the time to progression and overall survival of patients treated with this

regimen.

- Determine the safety and toxicity profile of SAHA in these patients.

- Determine, preliminarily, feasibility and clinical efficacy of SAHA using molecular

correlates in tissue, oral mucosa, and blood.

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Pathological diagnosis of transitional cell carcinoma of the bladder or other sites of

the urothelium

- Less than 25% component of other cell types (e. g., small cell, neuroendocrine, or

squamous cell carcinoma)

- Locally recurrent or metastatic disease

- Disease must have recurred or progressed on or subsequent to platinum-based

chemotherapy in the adjuvant or advanced setting

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1

dimension as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan

- Bone metastases allowed provided there is measurable nonosseous disease

- No known brain metastases

- Must be willing to undergo biopsy prior to study entry OR archival tumor tissue must

be available for classification and correlates

PATIENT CHARACTERISTICS:

- Life expectancy > 3 months

- ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Bilirubin normal

- AST and ALT ≤ 2. 5 times upper limit of normal (ULN) (5 times ULN if liver metastases

are present)

- Creatinine ≤ 1. 5 times ULN OR creatinine clearance ≥ 40 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No allergic reactions attributed to compounds of similar chemical or biological

composition to vorinostat (SAHA), including any of the following:

- Sodium butyrate

- Trichostatin A (TSA)

- Trapoxin (TPX)

- MS-27-275

- FR901228

- No uncontrolled intercurrent illness including, but not limited to, any of the

following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situations that would limit study compliance

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Prior second-line chemotherapy for this cancer allowed provided > 6 months elapsed

from the completion of first-line chemotherapy to start of second-line chemotherapy

- Any number of prior intravesical therapies for superficial bladder cancer allowed

- One prior experimental biologic therapy for metastatic urothelial cancer allowed

provided it was not an agent known to act through histone deacetylation or demethylation (e. g., sodium butyrate, trichostatin A, trapoxin, MS-27-275, or FR901228)

- More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas

or mitomycin C) and recovered

- No more than 2 prior cytotoxic chemotherapy regimens for urothelial transitional cell

cancer

- At least 2 weeks since prior valproic acid

- No other concurrent investigational agents

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent anticancer agents or therapies

City of Hope Comprehensive Cancer Center, Duarte, California 91010-3000, United States

City of Hope Medical Group, Pasadena, California 91105, United States

Contra Costa Regional Medical Center, Martinez, California 94553, United States

Tower Cancer Research Foundation, Beverly Hills, California 90211, United States

University of California Davis Cancer Center, Sacramento, California 95817, United States

USC/Norris Comprehensive Cancer Center and Hospital, Los Angeles, California 90033-0804, United States

Veterans Affairs Outpatient Clinic - Martinez, Martinez, California 94553, United States

UPMC Cancer Centers, Pittsburgh, Pennsylvania 15232, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: June 2006
Last updated: May 23, 2008