Erlotinib Before and After Surgery in Treating Patients With Muscle-Invasive Bladder Cancer

Study Overview
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Brief Summary
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RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving erlotinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving erlotinib after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well erlotinib works when given before and after surgery in treating patients with muscle-invasive bladder cancer.

Detailed Description
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OBJECTIVES: Primary Determine the effect of neoadjuvant erlotinib hydrochloride on histopathological, molecular, and genetic correlates in patients undergoing radical cystectomy for muscle-invasive bladder cancer. Secondary Determine the pathological complete response rate in surgical specimens from patients treated with this drug. Determine recurrence and progression rates after cystectomy (up to 2 years after surgery) in patients treated with neoadjuvant and adjuvant erlotinib hydrochloride. Determine 2- and 5-year disease-free, disease-specific, and overall survival rates in patients treated with this drug. Determine the safety of this drug in these patients. OUTLINE: This is an open-label study. Patients receive oral erlotinib hydrochloride once daily for 4 weeks. Patients then undergo radical cystectomy with curative intent. Within 12 weeks after surgery, patients resume oral erlotinib hydrochloride* once daily for up to 2 years in the absence of disease progression or unacceptable toxicity. Note: *Patients who are candidates for adjuvant chemotherapy (e.g., found to have pathologic stage T3 (pT3), Node positive (N+) disease) do not receive erlotinib hydrochloride after surgery. Tumor tissue is obtained at baseline (at the original or confirmatory transurethral resection of the bladder tumor) and at the time of cystectomy for analysis of drug-specific and tissue-based biomarkers by western blot, immunohistochemistry, and gene array techniques. Histopathological, molecular, and genetic correlates are analyzed to better understand the potential effects of the epidermal growth factor receptor (EGFR) inhibition in transitional cell carcinoma and to determine the effect of neoadjuvant erlotinib on gene expression. Tumor tissue is also evaluated by real-time polymerase chain reaction to confirm drug effects on expected targets and on EGFR expression, activity, and affected signaling pathways in the disease state and by microarray analysis to define expression phenotypes correlating with outcome, distinguish responders from nonresponders, and determine effects of drug treatment on gene expression in disease. Patients are followed periodically for up to 5 years after surgery.

Official Title
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A Phase II Study of Erlotinib (Tarceva®) in Patients With Muscle-Invasive Bladder Cancer Undergoing Radical Cystectomy

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Erlotinib
* Procedure: Radical Cystectomy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed muscle-invasive bladder cancer, meeting the following criteria: Clinical stage T2 disease No locally-extensive clinical stage T3 or T4 disease No metastatic disease (N+, M+) by physical exam or radiologic evaluation Must have undergone prior initial or confirmatory transurethral resection of the bladder tumor (TURBT) Candidate for and has agreed to undergo radical cystectomy with curative intent No non-transitional cell carcinoma histologies PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Granulocyte count > 1,500/mm³ Platelet count > 100,000/mm³ Bilirubin normal Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 times upper limit of normal Creatinine normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No contraindication to erlotinib hydrochloride or other tyrosine kinase inhibitors PRIOR CONCURRENT THERAPY: No prior radiotherapy or systemic chemotherapy for bladder cancer Prior single-dose mitomycin C allowed at the time of TURBT Prior 6- or 12-week course of adjuvant intravesical Bacillus Calmette-Guerin (BCG) therapy with or without recombinant interferon alfa-2a allowed At least 4 weeks since other prior or concurrent radiotherapy, chemotherapy, or hormonal therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erlotinib<br>erlotinib given before and after transurethral resection of a bladder tumor, TURBT | Drug: Erlotinib<br>* Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. In addition, patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression<br>* Other names: Tarceva;Procedure: Radical Cystectomy<br>* Will occur 4 weeks prior to dosing with erlotinib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EGFR Activation Signal (AKT2) Expression to Predict Sensitivity to Erlotinib | Determine the effect of neoadjuvant erlotinib hydrochloride on histopathological, molecular, and genetic correlates in patients undergoing radical cystectomy for muscle-invasive bladder cancer. Gene expression of pre-treatment and post-treatment tumor samples were analyzed to define molecular determinants of response or resistance to epidermal growth factor receptor (EGFR) inhibition. Both in vitro and in vivo EGFR-associated signatures were evaluated on pre-treatment bladder tumors. Candidate molecular determinants of sensitivity to EGFR inhibition were characterized and examined for their ability to predict sensitivity to EGFR inhibitors in vitro. | 4 weeks before treatment and 4 weeks post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response Rate | Determine the pathological complete response rate (P0 rate) after undergoing radical cystectomy (RC). Evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 4 weeks | 
| Disease Recurrence and Progression Rates After Cystectomy | To determine disease recurrence/progression rates after cystectomy in patients treated with erlotinib | 2 years | 
| Overall Survival Rate | The number of patients who remained alive and with no evidence of disease at the mean (range) follow-up of 24.8 months (3.0-36.6). | 25 months | 
| Number of Subjects Experiencing Adverse Events | The incidence of all toxicities observed during neoadjuvant and adjuvant treatment phase.Toxicity will be graded per the Common Terminology Criteria for Adverse Events (CTCAE) 2.0. | 4 weeks - 2 years following surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II bladder cancer, transitional cell carcinoma of the bladder