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Erlotinib Hydrochloride in Treating Patients With Bladder Cancer Undergoing Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02169284
Recruitment Status : Terminated
First Posted : June 23, 2014
Results First Posted : July 7, 2020
Last Update Posted : July 7, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
Bladder Carcinoma Recurrent Bladder Carcinoma Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Other: Pharmacological Study Other: Placebo Other: Quality-of-Life Assessment Procedure: Therapeutic Conventional Surgery Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Phase II Clinical Chemoprevention Trial of Weekly Erlotinib Before Bladder Cancer Surgery
Actual Study Start Date : October 1, 2014
Actual Primary Completion Date : March 30, 2018
Actual Study Completion Date : March 30, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

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
  • OSI-774
  • Tarceva

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

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: Pharmacological Study
Correlative studies

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Procedure: Therapeutic Conventional Surgery
Undergo TURBT or cystectomy




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. EGFR Phosphorylation in Neoplastic Bladder Epithelium 9-18 Hours Post-study Dose [ 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.

  2. Pharmacokinetic Parameters: Erlotinib in Blood [ Time Frame: Baseline, day 8, and day 16 (day of surgery) ]
    Will be summarized by treatment arm (and, if applicable, by visit) with appropriate descriptive statistics.

  3. Pharmacokinetic Parameters: OSI-420 in Blood [ Time Frame: Baseline, day 8, and day 16 (day of surgery) ]
    Will be summarized by treatment arm (and, if applicable, by visit) with appropriate descriptive statistics.

  4. Frequency of Urination Symptoms in Men Only, Graded According to International Prostate Symptom Score (I-PSS) [ Time Frame: Baseline up to 18 hours after last study drug dose (on day 28) ]
    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.

  5. Expression of E-cadherin [ Time Frame: At time of surgery (approximately day 16) ]
    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.

  6. Percentage of Cells Expressing Ki67 [ Time Frame: At time of surgery (approximately day 16) ]
    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.

  7. Difference Between Normal and Neoplastic Tissue Phosphorylated ERK [ Time Frame: At time of surgery (approximately day 16) ]
    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.

  8. Difference Between Normal and Neoplastic Tissue of p53 [ Time Frame: At time of surgery (approximately day 16) ]
    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.

  9. Difference Between Normal and Neoplastic Tissue of Let-7 [ Time Frame: At time of surgery (approximately day 16) ]
    A two-sample t-test with normalizing transformation if necessary or Wilcoxon rank-sum test will be used.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02169284


Locations
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United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Lahey Hospital and Medical Center
Burlington, Massachusetts, United States, 01805
United States, New York
University of Rochester
Rochester, New York, United States, 14642
United States, South Carolina
Carolina Urologic Research Center
Myrtle Beach, South Carolina, United States, 29572
United States, Texas
Urology San Antonio Research PA
San Antonio, Texas, United States, 78229
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Tracy Downs University of Wisconsin, Madison
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02169284    
Other Study ID Numbers: NCI-2014-01320
NCI-2014-01320 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HHSN261201200033I
N01-CN-2012-00033
CO12336 ( Other Identifier: University of Wisconsin Hospital and Clinics )
UWI2013-01-02 ( Other Identifier: DCP )
N01CN00033 ( U.S. NIH Grant/Contract )
P30CA014520 ( U.S. NIH Grant/Contract )
First Posted: June 23, 2014    Key Record Dates
Results First Posted: July 7, 2020
Last Update Posted: July 7, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Urinary Bladder Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Erlotinib Hydrochloride
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action