Combination Chemotherapy in Treating Patients With Advanced Bladder or Kidney Cancer

Phase I Trial of Dose-Dense Gemcitabine, Doxorubicin, Then Paclitaxel Plus Carboplatin In Patients With Transitional Cell Carcinoma of the Urothelium and Impaired Renal Function

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects of giving gemcitabine, doxorubicin, and paclitaxel together with carboplatin in treating patients with advanced bladder or kidney cancer and impaired kidney function.

OBJECTIVES:

• Determine the safety and toxicity of dose-dense carboplatin plus paclitaxel on a weekly schedule given in sequence after gemcitabine and doxorubicin in patients with renal impairment and metastatic or locally advanced transitional cell carcinoma of the urothelium.
• Observe the outcome of this sequential systemic chemotherapy in these patients, or following surgical resection as adjuvant therapy in patients in whom poor renal function precludes the use of cisplatin-based chemotherapy.

OUTLINE: This is a dose escalation study of carboplatin.

Patients receive gemcitabine IV over 10 minutes and doxorubicin IV over 15 minutes for 5 doses on weeks 1, 3, 5, 7, and 9. Filgrastim (G-CSF) is given subcutaneously on days 3 through 10 of each 2-week course. On week 11, patients receive paclitaxel and carboplatin IV over 1 hour weekly for 12 weeks.

Each cohort of 3 patients is entered on sequentially increasing doses of carboplatin. If any patient experiences dose limiting toxicity (DLT), then 6 patients are entered at that dose level. If 3 patients experience DLT at any dose level, the maximum tolerated dose has been surpassed and a total of 6 patients are treated at the previous level.

Patients are evaluated at week 16 and at end of study.

PROJECTED ACCRUAL: There will be 18-30 patients accrued into this study over 9-15 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed advanced transitional cell urothelial cancer

  • Clinical Stage IV: T any, N1-3, M0; T any, N any, M1; or cT4, Nx, M0 (bladder tumors)
  • Pathological Stage III or IV bladder cancer: T any, N1-3, M0; T3b, N0, M0; T4, N0, M0; and T4, Nx, M0
  • Pathological Stage III or IV urothelial cancer of the renal pelvis or ureter: T any, N1-3, M0; T3, N0, M0; T4, N0, M0; and surgery has been performed within 10 weeks of initiation of therapy

• Impaired renal function (See Renal function tests)

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100% OR
• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Granulocyte count at least 1,500/mm^3
• Platelet count at least 150,000/mm^3

Hepatic:

• Bilirubin less than 1.5 times normal
• Alkaline phosphatase less than 2 times normal
• SGOT less than 2 times normal

Renal:

• Creatinine greater than 1.5 mg/dL but no greater than 2.5 mg/dL OR
• Creatinine clearance 30-59 mL/min

Cardiovascular:

• Normal cardiac function by history, physical examination, and chest radiograph OR
• If prior cardiac disease, left ventricular ejection fraction must be at least 50% by radionuclide ventriculogram or echocardiogram
• No serious cardiac arrhythmias; including first, second, and third degree heart block
• No New York Heart Association class III or IV heart disease

Other:

• No uncontrolled infection
• No other active cancer, except nonmelanomatous skin cancer and in situ carcinoma of the cervix curatively treated
• Not pregnant
• Effective barrier contraception required for all fertile patients during and for 6 months after therapy (encouraged to continue for 2 years or longer)

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior systemic chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy to the bladder
• At least 4 weeks since any other prior radiotherapy

Surgery:

• See Disease Characteristics