S0400, FR901228 in Treating Patients With Advanced Cancer of the Urothelium

A Phase II Study of Depsipeptide (NSC-630176) In Patients With Advanced Transitional Cell Carcinoma Of The Urinary Tract Who Have Progressed After Receiving One Prior Chemotherapy Regimen For Advanced Disease

RATIONALE: Drugs used in chemotherapy, such as FR901228 (depsipeptide), work in different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: This phase II trial is studying how well FR901228 works in treating patients with advanced cancer of the urothelium that has progressed or recurred after receiving one chemotherapy regimen.

OBJECTIVES:

• Determine the response (confirmed complete and partial) in patients with advanced transitional cell carcinoma of the urothelium that has progressed after prior chemotherapy when treated with FR901228 (depsipeptide) .
• Determine progression-free and overall survival of patients treated with this drug.
• Determine the qualitative and quantitative toxic effects of this drug in these patients.
• Determine, preliminarily, the effects of this drug on reversing tumor promoter gene methylation in these patients.
• Correlate, preliminarily, tumor DNA in plasma with response or outcome in patients treated with this drug.

OUTLINE: This is a multicenter study.

Patients receive FR901228 (depsipeptide) IV over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients achieving a complete response receive 2 additional courses of treatment.

Patients are followed every 3 months for 1 year and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 20-40 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed transitional cell carcinoma of the urothelium (bladder, renal pelvis, ureter, or urethra)

  • Metastatic disease

    • Node-positive, non-metastatic disease that is unresectable is allowed

  • Poorly differentiated transitional cell carcinoma OR predominant transitional cell carcinoma with rare foci of squamous differentiation or rare foci of adenocarcinoma allowed

• The following histologic types are not allowed:

  • Adenocarcinoma
  • Small cell carcinoma
  • Sarcoma
  • Squamous cell carcinoma
  • Mixed adeno/squamous/transitional histology

• Measurable disease

  • At least 1 unidimensionally measurable lesion ≥ 2 cm by conventional techniques OR ≥ 1 cm by spiral CT scan
  • Soft tissue disease irradiated within the past 2 months is not considered measurable

• Disease progression or recurrence after 1, and only 1, prior systemic chemotherapy regimen that included cisplatin or carboplatin for metastatic disease

• Not curable by surgery or radiotherapy

• No known brain metastases

PATIENT CHARACTERISTICS:

Age

• Not specified

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• White blood cell (WBC) count ≥ 3,000/mm^3

Hepatic

• Aspartate aminotransferase (SGOT) / alanine aminotransferase (SGPT) ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin normal

Renal

• Creatinine ≤ 2 times ULN

Cardiovascular

• Corrected QT interval (QTc) < 500 msec
• Left ventricular ejection fraction (LVEF) > 40% by Multi Gated Acquisition Scan (MUGA)
• No New York Heart Association class III or IV congestive heart failure
• No myocardial infarction within the past year
• No uncontrolled dysrhythmias
• No poorly controlled angina
• No serious ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
• No left ventricular hypertrophy on EKG
• No other significant cardiac disease

Other

• Potassium ≥ 4 mmol/L
• Magnesium ≥ 2 mg/dL
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No prior allergic reaction to compounds of similar chemical or biological composition to FR901228 (depsipeptide)
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer in complete remission

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent immunotherapy

Chemotherapy

• See Disease Characteristics
• At least 28 days since prior chemotherapy
• No prior FR901228 (depsipeptide)
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent hormonal therapy

Radiotherapy

• See Disease Characteristics
• More than 28 days since prior radiotherapy
• No concurrent radiotherapy

Surgery

• More than 28 days since prior surgery

Other

• Recovered from all prior therapy
• More than 28 days since prior intravesical therapy
• No concurrent hydrochlorothiazide
• No concurrent agent that causes QTc prolongation
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational histone deacetylase inhibitor agents or drugs (e.g., sodium valproate)
• No other concurrent anticancer therapy