Bladder Cancer
Conditions
Keywords
stage II bladder cancer, transitional cell carcinoma of the bladder
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.
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.
Interventions
DRUGErlotinib
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
PROCEDURERadical Cystectomy
Will occur 4 weeks prior to dosing with erlotinib
Sponsors
OSI Pharmaceuticals
National Cancer Institute (NCI)
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| EGFR Activation Signal (AKT2) Expression to Predict Sensitivity to Erlotinib | 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
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response Rate | 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. |
| Disease Recurrence and Progression Rates After Cystectomy | 2 years | To determine disease recurrence/progression rates after cystectomy in patients treated with erlotinib |
| Overall Survival Rate | 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). |
| Number of Subjects Experiencing Adverse Events | 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. |
Countries
United States
Participant flow
Pre-assignment details
27 patients were screened, 23 patients were consented to the study; three of these patients were not subsequently enrolled due to ineligibility (1) and patient decision not to enroll in the trial (2).
Participants by arm
| Arm | Count |
|---|---|
| Erlotinib erlotinib given before and after transurethral resection of a bladder tumor, TURBT
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
Radical Cystectomy: Will occur 4 weeks prior to dosing with erlotinib | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Erlotinib |
|---|---|
| Age, Continuous | 67.1 years |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 15 Participants |
| Smoking Status Current | 7 Participants |
| Smoking Status Former | 10 Participants |
| Smoking Status Never | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 23 |
| other Total, other adverse events | 23 / 23 |
| serious Total, serious adverse events | 8 / 23 |
Outcome results
Primary
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.
Time frame: 4 weeks before treatment and 4 weeks post treatment
Population: Only patients with tumor samples with sufficient and high quality RNA were used to generate the in vivo signatures.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Downstaged Tumors | EGFR Activation Signal (AKT2) Expression to Predict Sensitivity to Erlotinib | -0.29 fold change |
| Not-downstaged | EGFR Activation Signal (AKT2) Expression to Predict Sensitivity to Erlotinib | 0.128 fold change |
Secondary
Disease Recurrence and Progression Rates After Cystectomy
To determine disease recurrence/progression rates after cystectomy in patients treated with erlotinib
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Downstaged Tumors | Disease Recurrence and Progression Rates After Cystectomy | 4 Participants |
Secondary
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.
Time frame: 4 weeks - 2 years following surgery
Population: All patients enrolled received the full 4-week neoadjuvant course of erlotinib. 12 patients continued on erlotinib in the adjuvant phase for a mean (range) duration of 29 (5-84) weeks.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Diarrea | 6 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Dry skin | 2 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Lower urinary tract symptoms | 4 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Haematuria | 2 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Anorexia | 6 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Vagal episode | 1 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Nausea | 3 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Stomatitus | 1 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Fatigue | 6 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Pneumonitis | 0 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Cough | 3 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Deep vein thrombosis | 0 Participants |
| Downstaged Tumors | Number of Subjects Experiencing Adverse Events | Rash | 15 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Deep vein thrombosis | 1 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Rash | 6 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Anorexia | 0 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Diarrea | 1 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Fatigue | 2 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Lower urinary tract symptoms | 0 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Nausea | 0 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Cough | 2 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Dry skin | 1 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Haematuria | 0 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Vagal episode | 1 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Stomatitus | 2 Participants |
| Not-downstaged | Number of Subjects Experiencing Adverse Events | Pneumonitis | 1 Participants |
Secondary
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).
Time frame: 25 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Downstaged Tumors | Overall Survival Rate | 10 Participants |
Secondary
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.
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Downstaged Tumors | Pathological Complete Response Rate | 5 Participants |