Erlotinib and Green Tea Extract (Polyphenon® E) in Preventing Cancer Recurrence in Former Smokers Who Have Undergone Surgery for Bladder Cancer

OBJECTIVES:

Primary

- Compare the effects of erlotinib vs green tea extract (Polyphenon® E) vs placebo on the
2-year recurrence rate in former smokers with resected superficial transitional cell
carcinoma of the bladder.

- Develop an effective chemopreventative strategy (as an adjunct to standard care) for
the medical management of superficial bladder cancer in these patients.

Secondary

- Determine the toxic effects associated with these drugs in these patients.

- Determine a safe and effective chemopreventative dose of erlotinib in these patients.

- Correlate the modulation of 1 or more biomarkers with bladder cancer recurrence and/or
progression in patients treated with these drugs.

- Determine the risk of clinical bladder cancer progression in patients treated with
these drugs.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients
are stratified according to disease stage (Ta vs T1 vs carcinoma in situ) and participating
center. Patients are randomized to 1 of 3 treatment arms.

- Arm I: Patients receive oral erlotinib and oral green tea extract (Polyphenon® E)
placebo once daily.

- Arm II: Patients receive oral green tea extract (Polyphenon® E) and oral erlotinib
placebo once daily.

- Arm III: Patients receive oral erlotinib placebo and oral green tea extract placebo
once daily.

In all arms, treatment continues for 12 months in the absence of disease recurrence or
unacceptable toxicity.

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

PROJECTED ACCRUAL: A total of 330 patients (110 per treatment arm) will be accrued for this
study within 3 years.

Inclusion Criteria:

- Participants must be former smokers and have ceased smoking at study entry.

- Participants with any previous history of prior cancer diagnosis of Grade 1, 2, or 3,
Ta or T1 papillary TCC, or CIS TCC, histologically confirmed, with a newly diagnosed
or recurrent tumor within 6 months of accrual who are rendered disease free by
standard of care. Patients with Grade 1 papillary tumors must meet at least one of
the following additional criteria:

1. multiple, synchronous tumors (>2)

2. a single tumor greater than 1 cm in size

- At study entry, patients must have no evidence of disease

- Participants may have been previously treated with intravesical therapy.

- Age>18 years

- Transurethral resection of bladder tumor within 6 months prior to entry on to study

- Participants must have a signed written informed consent

- Agreement with complete abstinence from heterosexual intercourse or with the use of
contraception during the treatment phase in women of childbearing potential

- Negative pregnancy test in women of childbearing potential

- Patients must have adequate bone marrow function at study entry (WBC>3000,
platelets>100000/mm3, and hemoglobin>10g/dl)

- Patients must have satisfactory renal and hepatic function, defined as plasma
creatinine of < 1.5mg/dl, total bilirubin < 1.5, and AST/ALT < 1.5 x the upper limit
of normal

- Patients with evidence of obstructive lung disease as the etiology of a low diffusing
capacity will still be eligible as long as the chest radiograph does not demonstrate
interstitial changes

Exclusion Criteria:

- Prior chemotherapy or radiotherapy

- Prior (within 2 years) or concurrent malignancies, except non-melanomatous skin
tumors or carcinoma in situ of the cervix

- Significant medical or psychiatric condition that would make the participant a poor
protocol candidate

- TCC greater than or equal to T2 at most recent diagnosis

- Involvement of the upper urinary tract prior to or at the time of initial tumor
resection

- Prior treatment with experimental drugs, high dose steroids, or with any other cancer
treatment within 4 weeks prior to the first dose of study drug and for the duration
of the study

- Positive pregnancy test at any time throughout the course of the study

- Normal consumption of greater than 5 cups of green tea daily

- Participants taking a known CYP 3A4 inducer or food products and medications known to
be inhibitors or metabolized by CYP3A4/5 such as erythromycin, ketoconazole, etc.
will be excluded since these drugs may be expected to result in altered exposure of
Erlotinib

- ECOG performance status > 1

- History of idiopathic pulmonary fibrosis or other interstitial lung disease

- Use of tricyclic antidepressants, including imipramine, dothiepin, and mianserin

- Use within the last 12 months of amiodarone, methotrexate, isoniazid, minocycline, or
nitrofurantoin

- History of environmental or occupational metal dust or wood dust exposure

- History of connective tissue disease, including scleroderma, rheumatoid arthritis,
Sjogren's Syndrome, or sarcoid

- Significant ophthalmologic abnormalities or patients using contact lenses

- Evidence of interstitial lung disease on chest radiograph

- Patients without obvious interstitial lung disease on chest radiograph will be
excluded if they have evidence of parenchymal restrictive lung disease on pulmonary
function testing as identified by the following criteria:

1. Both vital capacity and total lung capacity <80% of predicted value

2. A diffusing capacity of the lung for carbon monoxide, corrected for hemoglobin,
< 75% of predicted value