Phase II Clinical Chemoprevention Trial of Weekly Erlotinib Before Bladder Cancer Surgery
Overview
- Phase
- Phase 2
- Intervention
- Erlotinib Hydrochloride
- Conditions
- Bladder Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 50
- Locations
- 6
- Primary Endpoint
- EGFR Phosphorylation in Normal Appearing Bladder Epithelium Adjacent to Tumor
- Status
- Terminated
- Last Updated
- 5 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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%
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
- •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
Arms & Interventions
Group I (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Erlotinib Hydrochloride
Group I (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Laboratory Biomarker Analysis
Group I (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Pharmacological Study
Group I (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Quality-of-Life Assessment
Group I (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Therapeutic Conventional Surgery
Group II (placebo)
Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Laboratory Biomarker Analysis
Group II (placebo)
Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Pharmacological Study
Group II (placebo)
Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Placebo
Group II (placebo)
Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Quality-of-Life Assessment
Group II (placebo)
Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.
Intervention: Therapeutic Conventional Surgery
Outcomes
Primary Outcomes
EGFR Phosphorylation in Normal Appearing Bladder Epithelium Adjacent to Tumor
Time Frame: Up to 18 hours after last study drug dose (on day 28)
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.
Secondary Outcomes
- Pharmacokinetic Parameters: Erlotinib in Blood(Baseline, day 8, and day 16 (day of surgery))
- Difference Between Normal and Neoplastic Tissue Phosphorylated ERK(At time of surgery (approximately day 16))
- Pharmacokinetic Parameters: OSI-420 in Blood(Baseline, day 8, and day 16 (day of surgery))
- EGFR Phosphorylation in Neoplastic Bladder Epithelium 9-18 Hours Post-study Dose(Up to 18 hours after last study drug dose (on day 28))
- Frequency of Urination Symptoms in Men Only, Graded According to International Prostate Symptom Score (I-PSS)(Baseline up to 18 hours after last study drug dose (on day 28))
- Percentage of Cells Expressing Ki67(At time of surgery (approximately day 16))
- Difference Between Normal and Neoplastic Tissue of p53(At time of surgery (approximately day 16))
- Difference Between Normal and Neoplastic Tissue of Let-7(At time of surgery (approximately day 16))
- Expression of E-cadherin(At time of surgery (approximately day 16))