Erlotinib Hydrochloride in Treating Patients With Bladder Cancer Undergoing Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well erlotinib hydrochloride works in treating patients with bladder cancer undergoing surgery. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if there is a difference in EGFR phosphorylation in normal appearing bladder epithelium adjacent to tumor approximately 9-18 hours post-study dose, between patients randomized to erlotinib hydrochloride (erlotinib) weekly as compared to placebo. SECONDARY OBJECTIVES: I. Assess the tolerance of high dose weekly erlotinib compared to placebo. II. Assess the expression of phosphorylated EGF receptor in tumor tissue when available. III. Assess the expression of e-cadherin and Ki67 in normal and abnormal urothelium. IV. Assess the expression of phosphorylated ERK in normal and abnormal urothelium. V. Assess limited pharmacokinetics of weekly erlotinib. VI. Assess the expression of p53 in normal and abnormal urothelium. VII. Assess the expression of let-7 in normal and abnormal urothelium. VIII. Exploratory assessment of urination symptoms in men. OUTLINE: Patients are randomized to 1 of 2 treatment groups. GROUP I: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1, 8, and 15. Patients then undergo transurethral resection of bladder tumor (TURBT) or cystectomy on day 16. GROUP II: Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16. After completion of study treatment, patients are followed up for 7-14 days.

Official Title
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Phase II Clinical Chemoprevention Trial of Weekly Erlotinib Before Bladder Cancer Surgery

Conditions
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Bladder Carcinoma, Recurrent Bladder Carcinoma

Intervention / Treatment
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* Drug: Erlotinib Hydrochloride
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Placebo
* Other: Quality-of-Life Assessment
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a confirmed or suspected invasive or non-invasive bladder tumor (initial or recurrent) discovered on cystoscopy or radiologic imaging performed within 120 days of randomization Patients with muscle invasive bladder cancer (MIBC) must have never received and currently be ineligible for cisplatin-based neoadjuvant chemotherapy due to any of the following: Calculated creatinine clearance of < 60 ml/min Karnofsky performance status (KPS) < 80 Solitary kidney or Patient refusal to undergo neoadjuvant chemotherapy The participant may have prior treatment for bladder tumor (excluding radiation therapy) provided that treatment: Was completed greater than 30 days prior to the first dose of study agent Participants must be a candidate for a trans-urethral resection of the bladder tumor (TURBT), cystectomy (partial or radical) or cystoscopy with biopsy at a participating organization Karnofsky >= 60% White blood cells (WBC) >= 3000/mm^3 Platelets >= 100,000mm^3 Hemoglobin > 10 g/dL Alkaline phosphatase =< 1.5 x upper limit of normal Bilirubin =< 1.5 x upper limit of normal Aspartate aminotransferase (AST) =< 1.5 x upper limit of normal Alanine aminotransferase (ALT) =< 1.5 x upper limit of normal Bilirubin for Gilbert's =< 3.0 mg/dl A calculated creatinine clearance (Cockcroft Gault) of >= 30 ml/min Sodium >= 130 mg/dl and =< upper limit of normal Potassium >= 3.0 mg/dl and =< upper limit of normal Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Any treatment for the bladder tumor other than intravesical therapy between the pre-study cystoscopy or radiologic imaging which identified the suspected bladder tumor and the scheduled surgical removal or cystoscopy-guided biopsy of that tumor Any chemotherapy and/or radiation therapy received =< 3 months of study entry and any immunotherapy received =< 6 months of study entry (with the exception of Bacillus Calmette-Guerin [BCG] treatment) Any prior external beam radiation to the pelvis A concurrent skin rash or skin condition requiring treatment with a prescription medication The following medications may not be taken within 24 hours of the first dose of study agent or at any time while a participant is taking study agent Coumadin Strong CYP3A4 inhibitors including ketoconazole, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, dasabuvir, idelalisib, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or grapefruit juice CYP3A4 inducers including rifampicin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, primidone, enzalutamide, fosphenytoin, lumacaftor, mitotane, and St. John's wort Agents which decrease gastric acid are allowed but should be avoided if possible Participants may resume inhibitors or inducers of CYP3A4 > 14 days after their last dose of study agent Participants requiring daily use of non-steroidal anti-inflammatory drugs (NSAIDs), with the exception of =< 81 mg aspirin per day; during study participation, acetaminophen is preferred for treatment of pain; the use of NSAIDs, as needed for pain, is discouraged Participants may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib or clindamycin (topical agent for potential skin toxicity) An underlying predisposition to rectal or gastrointestinal bleeding or uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Females who are pregnant or lactating may not participate in this study; females of child-bearing potential must have a negative pregnancy test before starting study agent; patients who have had a bilateral oophorectomy, hysterectomy, or are greater than 1 year since their last menses are not considered to be of child-bearing potential

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (erlotinib hydrochloride)<br>Patients receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16. | Drug: Erlotinib Hydrochloride<br>* Given PO<br>* Other names: Tarceva;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Procedure: Therapeutic Conventional Surgery<br>* Undergo TURBT or cystectomy<br>|
| Placebo Comparator: Group II (placebo)<br>Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Procedure: Therapeutic Conventional Surgery<br>* Undergo TURBT or cystectomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EGFR Phosphorylation in Normal Appearing Bladder Epithelium Adjacent to Tumor | EGFR phosphorylation will be assessed using Immunohistochemistry (IHC), greater mean optical density is associated with greater phosphorylation. The difference between the placebo group and the erlotinib hydrochloride group will be tested as-randomized using a two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test. | Up to 18 hours after last study drug dose (on day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EGFR Phosphorylation in Neoplastic Bladder Epithelium 9-18 Hours Post-study Dose | EGFR phosphorylation will be assessed using Immunohistochemistry (IHC), greater mean optical density is associated with greater phosphorylation. | Up to 18 hours after last study drug dose (on day 28) | 
| Pharmacokinetic Parameters: Erlotinib in Blood | Will be summarized by treatment arm (and, if applicable, by visit) with appropriate descriptive statistics. | Baseline, day 8, and day 16 (day of surgery) | 
| Pharmacokinetic Parameters: OSI-420 in Blood | Will be summarized by treatment arm (and, if applicable, by visit) with appropriate descriptive statistics. | Baseline, day 8, and day 16 (day of surgery) | 
| Frequency of Urination Symptoms in Men Only, Graded According to International Prostate Symptom Score (I-PSS) | A well documented survey called the International Prostate Symptom Score (I-PSS) of urination symptoms which correlates with prostatic hyperplasia in men will be filled out by men at baseline and end of study. The I-PSS is an 8-item survey; 7 questions scored from 0-5 where 0 is 'none' or 'not at all' and 5 is 'five times' or 'almost always'. The sum of the scores for the first 7 questions has a total range of 0-35 where 0 is asymptomatic, 1-7 is mild symptoms, 8-19 is moderate symptoms, and 20-35 are severe symptoms. A final quality of life question is scored from 0-6 where 0 (delighted) to 6 (terrible). This question serves as a conversation starting point between the patient and physician. | Baseline up to 18 hours after last study drug dose (on day 28) | 
| Expression of E-cadherin | E-Cadherin expression will be assessed using Immunohistochemistry (IHC), greater membrane optical density was associated with greater expression. A two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | At time of surgery (approximately day 16) | 
| Percentage of Cells Expressing Ki67 | Ki-67 expression will be assessed using Immunohistochemistry (IHC), greater positivity was associated with greater expression. A two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | At time of surgery (approximately day 16) | 
| Difference Between Normal and Neoplastic Tissue Phosphorylated ERK | Phosphorylated ERK will be assessed using Immunohistochemistry (IHC), greater mean optical density is associated with greater expression. A two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | At time of surgery (approximately day 16) | 
| Difference Between Normal and Neoplastic Tissue of p53 | p53 expression will be assessed using Immunohistochemistry (IHC), greater nucleus optical density and positivity was associated with greater expression. A two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | At time of surgery (approximately day 16) | 
| Difference Between Normal and Neoplastic Tissue of Let-7 | A two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used. | At time of surgery (approximately day 16) |