Erlotinib Hydrochloride in Treating Participants With Muscle Invasive or Recurrent Urothelial Cancer

PRIMARY OBJECTIVES:

I. To estimate the response rate (ie: pT0 rate) of patients with urothelial cancer treated
with erlotinib prior to cystectomy.

SECONDARY OBJECTIVES:

I. To estimate the 4-year disease-free survival of patients with urothelial cancer treated
with erlotinib prior to cystectomy.

II. To measure epithelial-mesenchymal transition (EMT) markers (E-cadherin, HER4, PDGFR-beta,
vimentin, fibronectin) in pre- and post-treatment biopsies and correlate expression patterns
with the biological responses measured below.

III. To quantify target inhibition, antiproliferation (KI-67), and apoptosis (terminal
deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) in biopsies obtained from
patients before, during, and after therapy.

IV. Interrogate membrane (phosphorylated EGFR) and downstream receptor signaling pathways
(ERKs, AKT/mTOR, GSK-3beta) to provide further insight into whether or not a given tumor
displays a biological response.

V. To correlate the changes in Ki-67 expression with changes in angiogenesis and angiogenesis
related gene expression utilizing fluorescent tissue staining techniques that we have
developed in the laboratory (such as two-color TUNEL, phosphor-receptor, and microvessel
density.) VI. To profile messenger ribonucleic acid (mRNA) expression in pre- and
post-treatment biopsies using Affymetrix arrays and correlate the changes observed with EMT,
growth arrest, and apoptosis.

VII. To quantify EGFR copy number and correlate with changes observed with EMT, growth
arrest, and apoptosis.

OUTLINE:

Participants receive erlotinib hydrochloride orally (PO) once daily (QD) for 3-5 weeks in the
absence of disease progression or unacceptable toxicity. Within 24 hours of the last dose,
participants undergo cystectomy.

After completion of study treatment, participants are followed up every 6 months for 1 year,
then annually for 4 years.

Inclusion Criteria:

- Patients must have histologic proof of urothelial cancer. This includes bladder
cancer, in addition to other tumors of the urothelial lining including renal pelvis,
ureteral, and urethral cancer. This group may include any patient requiring
cystectomy, including patients with recurrent or extensive superficial disease
(cTa-T1N0M0), CIS (carcinoma in situ), or muscle invasive disease (cT2-3aN0M0), whose
tumor could not be completely removed at transurethral resection

- Patients with the following high-risk features: Micropapillary features (more than
focal on pathology); Small cell carcinoma; 3-dimensional (D) mass on exam under
anesthesia (EUA); Lymphovascular invasion; Hydronephrosis (unless in the opinion of
the treating physician, this is not due to tumor); High grade (grade 3) tumors of the
ureter, renal pelvis, or urethra, or tumors in these areas with radiographic
abnormality large enough to recognize as an abnormal mass by computed tomography (CT)
or magnetic resonance imaging (MRI) imaging; Direct invasion of the prostatic stroma
or the vaginal wall (ie: cT4a disease) should be offered neoadjuvant cytoreductive
chemotherapy (ie: cisplatin-based). Patients refusing or who are not considered
candidates for cytoreductive chemotherapy may be considered eligible. Dr.
Siefker-Radtke will be the final arbiter in determining eligibility for the trial

- Please note that the presence of variant histologic subtypes is acceptable, except in
the case for small cell variant which is traditionally treated with cytoreductive
chemotherapy. Patients with small cell who refuse recommended cytoreductive
chemotherapy may still be considered eligible

- Patients must have an evaluation in the department of urology, and be deemed an
acceptable surgical candidate

- Patients must NOT have clinical evidence of metastatic disease by either CT or MRI of
the abdomen and pelvis, and chest x-ray. In the absence of a bone scan, patients
should be free of bone pain and have an alkaline phosphatase < 1.5 x upper limit of
normal (ULN) of the upper limit of normal, or a normal bone fraction of alkaline
phosphatase. If these features are present, patients should have a bone scan and this
should be interpreted as showing no evidence of metastatic disease in order to be
eligible

- Patients, 18 years and older, must either be not of child bearing potential or have a
negative pregnancy test within 2 weeks of treatment. Patients are considered not of
child bearing potential if they are surgically sterile (they have undergone a
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
postmenopausal

- Absolute neutrophil count (ANC) >= 1,000/ul

- Platelets >= 75,000/microliters

- Creatinine =< 2.0 x institutional upper limit of normal (ULN), or a creatinine
clearance of > 30 ml/min as calculated by Cockroft-Gault or by 24-hour urine
collection

- Bilirubin =< 2.5 x ULN

- Aspartate aminotransferase (AST) =< 5.0 x ULN

- Zubrod performance status (PS) =< 2

- Patients with second malignancies are eligible provided that the expected outcome from
the second cancer is such that this will not interfere in the delivery of this
therapy, or in doing cystectomy, and provided that the expectation of survival from
any prior malignancy is reliably > 4 years

Exclusion Criteria:

- Acute hepatitis or known human immunodeficiency virus (HIV)

- Active or uncontrolled infection

- Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension,
unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled
congestive heart failure, and cardiomyopathy with decreased ejection fraction =< 40%

- Prior therapy specifically and directly targeting the EGFR pathway

- Patients with interstitial lung disease

- Any concurrent chemotherapy not indicated in the study protocol or any other
investigational agent(s)

- Patients with metastatic or surgically unresectable disease are not eligible for this
study. In addition, patients who do not agree to surgery are not eligible for this
trial

- Patients who have received prior systemic chemotherapy or radiation therapy for
urothelial cancer are not eligible. Any prior intravesical chemotherapy is allowed