Erlotinib Hydrochloride in Treating Patients With Bladder Cancer Undergoing Surgery

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

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.

Study Overview

• Status: Terminated
• Conditions: Bladder Carcinoma; Recurrent Bladder Carcinoma
• Intervention / Treatment: Drug: Erlotinib Hydrochloride; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Other: Placebo; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
  • Texas
    • San Antonio, Texas, United States, 78229
      • Urology San Antonio Research PA
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Erlotinib Hydrochloride; Given PO; Other Names: Cp-358,774; Tarceva; OSI-774; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Pharmacological Study; Correlative studies; Procedure: Therapeutic Conventional Surgery; Undergo TURBT or cystectomy
Placebo Comparator: Group II (placebo); Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Placebo; Given PO; Other Names: placebo therapy; PLCB; sham therapy; Other: Pharmacological Study; Correlative studies; Procedure: Therapeutic Conventional Surgery; Undergo TURBT or cystectomy

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Tracy Downs, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): March 30, 2018
• Study Completion (Actual): March 30, 2018

Study Registration Dates

• First Submitted: June 19, 2014
• First Submitted That Met QC Criteria: June 19, 2014
• First Posted (Estimate): June 23, 2014

Study Record Updates

• Last Update Posted (Actual): July 7, 2020
• Last Update Submitted That Met QC Criteria: June 24, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Carcinoma; Urinary Bladder Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: NCI-2014-01320 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA014520 (U.S. NIH Grant/Contract); N01-CN-2012-00033; N01CN00033 (U.S. NIH Grant/Contract); HHSN261201200033I; CO12336 (Other Identifier: University of Wisconsin Hospital and Clinics); UWI2013-01-02 (Other Identifier: DCP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No