Gefitinib Plus Combination Chemotherapy in Treating Patients With Locally Advanced or Metastatic Bladder Cancer

PRIMARY OBJECTIVES:

I. To describe the overall response proportion in patients with advanced carcinoma of the urothelial tract treated with cisplatin, gemcitabine (gemcitabine hydrochloride) and ZD1839 (gefitinib), given on a 21 day schedule, followed by maintenance ZD1839.

SECONDARY OBJECTIVES:

I. To describe the time to progression, progression-free survival, and overall survival in patients with advanced carcinoma of the urothelial tract treated with cisplatin, gemcitabine and ZD1839, given on a 21 day schedule, followed by maintenance ZD1839.

II. To evaluate the effect of epidermal growth factor receptor (EGFR) expression level on overall response rate and progression-free survival in patients with advanced carcinoma of the urothelial tract treated with cisplatin, gemcitabine and ZD1839, given on a 21 day schedule, followed by maintenance ZD1839.

III. To assess the toxicity of the combination of cisplatin, gemcitabine and ZD1839 given on a 21 day schedule, followed by maintenance ZD1839 in patients with advanced carcinoma of the urothelial tract.

OUTLINE: This is a multicenter study.

Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1 and 8 and cisplatin IV over 1 hour on day 1. Patients also receive gefitinib orally (PO) once daily (QD) beginning on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve complete remission, partial remission, or maintain stable disease continue gefitinib PO QD for 5 years or until disease progression or unacceptable toxicity occurs.

Patients are followed at least every 3 months for 1 year and then at least every 6 months until disease progression or relapse.

Inclusion criteria

• Biopsy proven transitional cell carcinoma of the urothelial tract (bladder, ureter, renal pelvis or urethra); histologic documentation of metastatic/recurrent disease is not required; clinical, but not pathologic staging, is required
• Metastatic (N2, N3 or M1) urothelial tract carcinoma; patients must not be candidates for potentially curative surgery or radiation therapy
• Patients must have measurable disease as defined below:

• Measurable disease: lesions 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 computed tomography (CT) scan; the bladder is not a site of measurable disease
• Non-measurable disease: all other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions; lesions that are considered non-measurable include the following:

• Bone lesions
• Leptomeningeal disease
• Ascites
• Pleural/pericardial effusion
• Inflammatory breast disease
• Lymphangitis cutis/pulmonis
• Abdominal masses that are not confirmed and followed by imaging techniques
• Cystic lesions
• Prior treatment:

• No prior systemic chemotherapy except single-agent chemotherapy used as a radiosensitization agent; prior intravesical chemotherapy is permissible; prior adjuvant or neoadjuvant chemotherapy is not permissible
• No prior systemic therapy for advanced urothelial carcinoma including investigational therapies such as, but not limited to, agents targeting the HER2/neu, signal transduction (including EGFR), angiogenic, immune, and cell cycle pathways
• No prior treatment with ZD1839
• > 4 weeks and fully recovered from major surgery, radiation, or intravesical chemotherapy
• Tumor tissue from the primary tumor or from biopsy of a metastatic site must be available for EGFR expression determination; when tissue specimens from both primary and metastatic sites are available, both must be submitted for EGFR testing; expression of EGFR is not required
• No cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers within 7 days prior to starting protocol therapy and while on protocol treatment; CYP3A4 inducers include phenytoin, carbamazepine, barbiturates, rifampin, St John's Wort, dexamethasone, modafinil, and rifapentine; single doses of dexamethasone used as an antiemetic are permitted
• No evidence of brain metastases
• Patient must have no evidence of:

• > grade 1 pre-existing sensory or motor neuropathy
• Active severe chronic gastrointestinal disorders including liver disease, diarrheal or emetic disorders, or malabsorptive conditions causing nausea or diarrhea
• Active severe chronic desquamative cutaneous disorder
• Active severe corneal disease or inflammatory ocular disorder
• No "currently active" second malignancy other than non-melanoma skin cancers; patients are not considered to have a "currently active" malignancy if they have completed therapy and considered by their physician to be at less than 30% risk of relapse
• No patients with 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
• No human immunodeficiency virus (HIV) disease
• Common Toxicity Criteria (CTC) (Eastern Cooperative Oncology Group [ECOG]) performance status 0-2
• Granulocytes >= 1,500/ul
• Platelet count >= 100,000/ul
• Bilirubin =< 1.25 x upper limits of normal
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.0 x upper limits of normal
• Calculated creatinine clearance >= 50 ml/min

Exclusion criteria

• Patients must not be pregnant or engaged in nursing; men and women of reproductive age must agree to practice effective contraception in order to participate in this study