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

• ClinicalTrials.gov Identifier: NCT00380029
• Recruitment Status: Completed
• First Posted: September 25, 2006
• Results First Posted: June 19, 2017
• Last Update Posted: July 19, 2017
• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: OSI Pharmaceuticals; National Cancer Institute (NCI)
• Information provided by (Responsible Party): UNC Lineberger Comprehensive Cancer Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Bladder Cancer	Drug: Erlotinib; Procedure: Radical Cystectomy	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Erlotinib (Tarceva®) in Patients With Muscle-Invasive Bladder Cancer Undergoing Radical Cystectomy
• Study Start Date: May 2006
• Actual Primary Completion Date: August 2010
• Actual Study Completion Date: June 2014

Arms and Interventions

Arm

Intervention/treatment

Experimental: Erlotinib; erlotinib given before and after transurethral resection of a bladder tumor, TURBT

Drug: Erlotinib; 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; Other Name: Tarceva; Procedure: Radical Cystectomy; Will occur 4 weeks prior to dosing with erlotinib

Outcome Measures

Primary Outcome Measures :

1. EGFR Activation Signal (AKT2) Expression to Predict Sensitivity to Erlotinib [ Time Frame: 4 weeks before treatment and 4 weeks post treatment ]
   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.

Secondary Outcome Measures :

1. Pathological Complete Response Rate [ Time Frame: 4 weeks ]
   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.
2. Disease Recurrence and Progression Rates After Cystectomy [ Time Frame: 2 years ]
   To determine disease recurrence/progression rates after cystectomy in patients treated with erlotinib
3. Overall Survival Rate [ Time Frame: 25 months ]
   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).
4. Number of Subjects Experiencing Adverse Events [ Time Frame: 4 weeks - 2 years following surgery ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, North Carolina

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States, 27599-7295

Sponsors and Collaborators

UNC Lineberger Comprehensive Cancer Center

OSI Pharmaceuticals

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Raj S. Pruthi, MD; UNC Lineberger Comprehensive Cancer Center

More Information

Additional Information:

UNC Lineberger Comprehensive Cancer Center 

Publications of Results:

Pruthi RS, Nielsen M, Heathcote S, Wallen EM, Rathmell WK, Godley P, Whang Y, Fielding J, Schultz H, Grigson G, Smith A, Kim W. A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and pathological results. BJU Int. 2010 Aug;106(3):349-54. doi: 10.1111/j.1464-410X.2009.09101.x. Epub 2010 Jan 19.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00380029
• Other Study ID Numbers: LCCC 0521; P30CA016086 ( U.S. NIH Grant/Contract )
• First Posted: September 25, 2006
• Results First Posted: June 19, 2017
• Last Update Posted: July 19, 2017
• Last Verified: June 2017

Keywords provided by UNC Lineberger Comprehensive Cancer Center:

stage II bladder cancer; transitional cell carcinoma of the bladder

Additional relevant MeSH terms:

Urinary Bladder Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Urinary Bladder Diseases; Urologic Diseases; Erlotinib Hydrochloride; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action