A Phase III Study of IRESSA in Combination With Intravesical BCG Versus Intravesical BCG Alone in High Risk Superficial Transitional Cell Carcinoma of the Bladder
A Phase III Study of IRESSA in Combination With Intravesical BCG Versus Intravesical BCG Alone in High Risk Superficial Transitional Cell Carcinoma of the Bladder
RATIONALE: Biological therapies, such as BCG, may stimulate the immune system in different ways and stop tumor cells from growing. Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving BCG together with gefitinib may kill more tumor cells. It is not yet known whether BCG is more effective with or without gefitinib in treating bladder cancer.
PURPOSE: This randomized phase III trial is studying BCG and gefitinib to see how well they work compared to BCG alone in treating patients with high-risk bladder cancer.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a randomized, prospective, open-label, controlled, multicenter study. Patients are stratified according to study center, status of tumor (primary vs recurrent), carcinoma in situ (yes vs no), prior BCG therapy (yes vs no), and single dose of intravesical mitomycin C at the time of the most recent transurethral resection (yes vs no). Patients are randomized to 1 of 2 treatment arms.
In both arms, treatment with maintenance therapy repeats at 3, 6, 12, 18, 24, 30, and 36 months for a total of 7 courses in the absence of disease progression or unacceptable toxicity.
Quality of life is assessed at baseline, periodically during study therapy, and then at 3 and 6 months after completion of study therapy.
After study completion, patients are followed every 3 months for 2 years, every 6 months for 4 years, and then annually thereafter.
PROJECTED ACCRUAL: A total of 166 patients will be accrued for this study.
DISEASE CHARACTERISTICS:
Histologically confirmed transitional cell carcinoma (TCC) of the bladder meeting ≥ 1 of the following criteria:
Noninvasive papillary carcinoma (Ta) with ≥ 1 of the following characteristics:
Carcinoma in situ (Tis)
At least grade 2 tumor that invades the subepithelial connective tissue (T1)
Has undergone TUR of all visible bladder lesions within the past 21 to 60 days with biopsy of the underlying bladder wall for all tumors and cold-cup biopsy of all suspicious areas
No metastatic disease as confirmed by negative radiology within the past 16 weeks, including the following:
Chest x-ray
Imaging of the upper urinary tract by 1 of the following methods:
No evidence of TCC of the upper urinary tract
No mixed histology of bladder cancer (i.e., TCC and squamous cell carcinoma of the bladder or TCC and small cell carcinoma of the bladder) at the most recent TUR
PATIENT CHARACTERISTICS:
ECOG performance status 0-2
Life expectancy > 5 years
Negative routine urine microscopy and negative urine culture within the past 14 days
Willing to complete quality of life questionnaires in English or French
WBC ≥ 3,000/mm³
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT ≤ 1.5 times ULN
Alkaline phosphatase ≤ 1.5 times ULN
Creatinine ≤ 1.5 times ULN
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after study completion
No significant history of cardiac disease including, but not limited to, any of the following:
No active urinary tract infection
No active infection, including tuberculosis
No serious underlying medical conditions that would impair the ability of the patient to receive protocol treatment
No febrile illness or gross hematuria
No impaired immune response from any cause (congenital, therapy, or disease)
No clinically significant or untreated ophthalmologic condition (e.g., Sjögren's syndrome)
No gastrointestinal conditions (e.g., Crohn's disease or ulcerative colitis)
No history of psychiatric or neurological disorder that would limit study compliance
No other malignancies except for adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years
No contraindications to spinal or general anesthesia as required for a TUR
No known hypersensitivity to BCG or gefitinib
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to the study drugs
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
More than 12 months since prior intravesical immunotherapy (including BCG +/- interferon)
More than 6 months since prior intravesical chemotherapy (including mitomycin C, thiotepa, doxorubicin hydrochloride)
No other prior or concurrent immune modulator therapy
No prior pelvic radiation
No prior gefitinib
No other concurrent experimental anticancer drugs
No concurrent use of drugs that induce CYP3A4 enzymes that have been shown to significantly reduce plasma concentrations of gefitinib (including phenytoin, carbamazepine, barbiturates, rifampin, or Hypericum perforatum [St. John's wort])
No concurrent grapefruit juice