Erlotinib Hydrochloride in Treating Patients With Bladder Cancer Undergoing Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT02169284
• Collaborator: (none)
• Enrollment: 50
• Locations: 6
• Arms: 2
• Actual Duration (Months): 41.9
• Patients Per Site: 8.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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:

1. 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:

1. Assess the tolerance of high dose weekly erlotinib compared to placebo. II. Assess the expression of phosphorylated EGF receptor in tumor tissue when available.

2. Assess the expression of e-cadherin and Ki67 in normal and abnormal urothelium.

3. Assess the expression of phosphorylated ERK in normal and abnormal urothelium.

4. 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 Design

• Study Type: Interventional
• 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: Oct 1, 2014
• Actual Primary Completion Date: Mar 30, 2018
• Actual Study Completion Date: Mar 30, 2018

Arms and Interventions

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 Names: 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 Names: Quality of Life Assessment ; Procedure: Therapeutic Conventional Surgery; Undergo TURBT or cystectomy

Outcome Measures

Primary Outcome Measures

1. EGFR Phosphorylation in Normal Appearing Bladder Epithelium Adjacent to Tumor [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 [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 [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 [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) [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 [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
2	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
3	University of Rochester	Rochester	New York	United States	14642
4	Carolina Urologic Research Center	Myrtle Beach	South Carolina	United States	29572
5	Urology San Antonio Research PA	San Antonio	Texas	United States	78229
6	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tracy Downs, University of Wisconsin, Madison

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 28, 2017

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02169284
• Other Study ID Numbers: NCI-2014-01320; NCI-2014-01320; HHSN261201200033I; N01-CN-2012-00033; CO12336; UWI2013-01-02; N01CN00033; P30CA014520
• First Posted: Jun 23, 2014
• Last Update Posted: Jul 7, 2020
• Last Verified: Jun 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Erlotinib Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	50 were consented, 13 participants ineligible

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Period Title: Overall Study
STARTED	24	13
COMPLETED	24	12
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)	Total
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Total of all reporting groups
Overall Participants	24	13	37
Age, Customized (years) [Mean (Full Range) ]
Participant Age	70.25	69.32	69.93
Sex: Female, Male (Count of Participants)
Female	3 12.5%	3 23.1%	6 16.2%
Male	21 87.5%	10 76.9%	31 83.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.2%	2 15.4%	3 8.1%
Not Hispanic or Latino	23 95.8%	11 84.6%	34 91.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 8.3%	0 0%	2 5.4%
White	22 91.7%	13 100%	35 94.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%	13 100%	37 100%
Karnofsky Performance Status (Count of Participants)
80	1 4.2%	0 0%	1 2.7%
90	4 16.7%	3 23.1%	7 18.9%
100	19 79.2%	10 76.9%	29 78.4%
Ever Smoked (Count of Participants)
Yes	21 87.5%	11 84.6%	32 86.5%
No	3 12.5%	2 15.4%	5 13.5%
Current Smoker (Count of Participants)
Yes	6 25%	3 23.1%	9 24.3%
No	18 75%	10 76.9%	28 75.7%
Systolic Blood Pressure (mmHg) [Mean (Full Range) ]
Mean (Full Range) [mmHg]	134.62	136.69	135.35
Diastolic Blood Pressure (mmHg) [Mean (Full Range) ]
Mean (Full Range) [mmHg]	76.62	78.23	77.19
Pulse (beats per minute) [Mean (Full Range) ]
Mean (Full Range) [beats per minute]	74.75	69.85	73.03
Temperature (degrees Fahrenheit) [Mean (Full Range) ]
Mean (Full Range) [degrees Fahrenheit]	97.67	97.48	97.61
Height (cm) [Mean (Full Range) ]
Mean (Full Range) [cm]	174.77	174.40	174.64
Weight (kg) [Mean (Full Range) ]
Mean (Full Range) [kg]	89.67	86.83	88.67
Body Mass Index (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	29.37	28.25	28.96
Medical History / Baseline Presence of Abnormality or Disease (participants) [Number]
Genitalia	1 4.2%	2 15.4%	3 8.1%
Prostate	2 8.3%	1 7.7%	3 8.1%
Musculoskeletal	2 8.3%	0 0%	2 5.4%
Skin	2 8.3%	0 0%	2 5.4%
Abdomen	1 4.2%	0 0%	1 2.7%
Appearance	0 0%	1 7.7%	1 2.7%
Head, Eyes, Ears, Nose, Throat	1 4.2%	0 0%	1 2.7%
Heart	1 4.2%	0 0%	1 2.7%
Lungs	1 4.2%	0 0%	1 2.7%
Vascular	1 4.2%	0 0%	1 2.7%
Breasts	0 0%	0 0%	0 0%
Chest	0 0%	0 0%	0 0%
Lymph Nodes	0 0%	0 0%	0 0%
Neurologic	0 0%	0 0%	0 0%
Pelvis	0 0%	0 0%	0 0%
Rectal	0 0%	0 0%	0 0%
Thyroid	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	EGFR Phosphorylation in Normal Appearing Bladder Epithelium Adjacent to Tumor
Description	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.
Time Frame	Up to 18 hours after last study drug dose (on day 28)

Outcome Measure Data

Analysis Population Description

Number analyzed differs from number of participants in each arm for two reasons: sample size insufficient for analysis and sample not obtained.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	15	8
Nucleus P-EGFR in Benign Tissue	0.216 (0.063)	0.181 (0.073)
Cytoplasm P-EGFR in Benign Tissue	0.159 (0.046)	0.133 (0.062)
Membrane P-EGFR in Benign Tissue	0.179 (0.053)	0.148 (0.074)
Entire Cell P-EGFR in Benign Tissue	0.190 (0.054)	0.159 (0.069)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Nucleus P-EGFR in benign tissue between erlotinib and placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.208
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Cytoplasm P-EGFR in benign tissue between erlotinib and placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.208
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Membrane P-EGFR in benign tissue between erlotinib and placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.272
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Entire Cell P-EGFR in benign tissue between erlotinib and placebo
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.220
	Comments
	Method	Wilcoxon rank-sum test
	Comments

2. Secondary Outcome

Title	EGFR Phosphorylation in Neoplastic Bladder Epithelium 9-18 Hours Post-study Dose
Description	EGFR phosphorylation will be assessed using Immunohistochemistry (IHC), greater mean optical density is associated with greater phosphorylation.
Time Frame	Up to 18 hours after last study drug dose (on day 28)

Outcome Measure Data

Analysis Population Description

Number analyzed differs from number of participants in each arm for two reasons: sample size insufficient for analysis and sample not obtained.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Patients receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16. Erlotinib Hydrochloride: Given PO Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies Therapeutic Conventional Surgery: Undergo TURBT or cystectomy	Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Placebo: Given PO Quality-of-Life Assessment: Ancillary studies Therapeutic Conventional Surgery: Undergo TURBT or cystectomy
Measure Participants	21	11
Nucleus P-EGFR Tumor Tissue	0.175 (0.060)	0.155 (0.059)
Cytoplasm P-EGFR Tumor Tissue	0.161 (0.053)	0.146 (0.070)
Membrane P-EGFR Tumor Tissue	0.170 (0.058)	0.154 (0.072)
Entire Cell P-EGFR Tumor Tissue	0.170 (0.056)	0.151 (0.061)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Nucleus P-EGFR in Tumor Tissue, p-value between placebo and Erlotinib
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.361
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Cytoplasm P-EGFR in Tumor Tissue, p-value between placebo and Erlotinib
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.383
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Membrane P-EGFR in Tumor Tissue, p-value between placebo and Erlotinib
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.427
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Entire Cell P-EGFR in Tumor Tissue, p-value between placebo and Erlotinib
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.416
	Comments
	Method	Wilcoxon rank-sum test
	Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Number analyzed differs from number of participants in each arm for two reasons: sample size insufficient for analysis and sample not obtained.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	24	13
Baseline	0.0 (0.0)	0.0 (0.0)
Day 8	169.7 (581.3)	0.0 (0.0)
Day 16 (Surgery)	2218.4 (1096.1)	0.3 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Baseline visit - p-value between erlotinib and placebo arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Day 8 - p-value between erlotinib and placebo arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.199
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Surgery visit - p-value between erlotinib and placebo arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon rank-sum test
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Number analyzed differs from number of participants in each arm for two reasons: sample size insufficient for analysis and sample not obtained.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	24	13
Baseline	0.0 (0.0)	0.0 (0.0)
Day 8	2.5 (7.3)	0.0 (0.0)
Day 16 (Surgery)	44.4 (34.6)	0.0 (0.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Baseline visit - p-value between erlotinib and placebo arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Day 8 - p-value between erlotinib and placebo arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.288
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Surgery visit - p-value between erlotinib and placebo arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon rank-sum test
	Comments

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

A participant in the placebo group had no survey response at baseline.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	15	7
Mild (score of 1-7)	7 29.2%	3 23.1%
Moderate (score of 8-19)	7 29.2%	3 23.1%
Severe (score of 20-35)	1 4.2%	0 0%
Mild (score of 1-7)	7 29.2%	5 38.5%
Moderate (score of 8-19)	7 29.2%	2 15.4%
Severe (score of 20-35)	1 4.2%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	P-value between groups at Baseline
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.792
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	P-value between groups at surgery visit
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.261
	Comments
	Method	Wilcoxon rank-sum test
	Comments

6. Secondary Outcome

Title	Expression of E-cadherin
Description	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.
Time Frame	At time of surgery (approximately day 16)

Outcome Measure Data

Analysis Population Description

Number analyzed differs from number of participants in each arm for two reasons: sample size insufficient for analysis and sample not obtained.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	15	9
Benign Tissue	0.615 (0.126)	0.572 (0.198)
Tumor Tissue	0.616 (0.070)	0.563 (0.079)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Expression of e-cadherin in Benign Tissue, P-Value between arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.721
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Expression of e-cadherin in Tumor Tissue, P-Value between arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.108
	Comments
	Method	Wilcoxon rank-sum test
	Comments

7. Secondary Outcome

Title	Percentage of Cells Expressing Ki67
Description	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.
Time Frame	At time of surgery (approximately day 16)

Outcome Measure Data

Analysis Population Description

Number analyzed differs from number of participants in each arm for two reasons: sample size insufficient for analysis and sample not obtained.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	15	9
Benign Tissue	0.093 (0.142)	0.080 (0.111)
Tumor Tissue	0.148 (0.142)	0.170 (0.137)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Expression of KI-67 in Benign Tissue, P-Value between arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.444
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Expression of KI-67 in Tumor Tissue, P-Value between arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.663
	Comments
	Method	Wilcoxon rank-sum test
	Comments

8. Secondary Outcome

Title	Difference Between Normal and Neoplastic Tissue Phosphorylated ERK
Description	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.
Time Frame	At time of surgery (approximately day 16)

Outcome Measure Data

Analysis Population Description

Number analyzed differs from number of participants in each arm for two reasons: sample size insufficient for analysis and sample not obtained.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	12	5
Nucleus P-ERK Normal-Tumor	-0.071 (0.167)	-0.077 (0.183)
Cytoplasm P-ERK Normal-Tumor	-0.104 (0.187)	-0.098 (0.170)
Entire Cell P-ERK Normal-Tumor	-0.084 (0.171)	-0.085 (0.173)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Difference in p-ERK between Normal and Tumor Tissue, P-Value between arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Difference in Cytoplasm p-ERK between Normal and Tumor Tissue, P-Value between arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.792
	Comments
	Method	Wilcoxon rank-sum test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments	Difference in Entire Cell p-ERK between Normal and Tumor Tissue, p-value between arms
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Wilcoxon rank-sum test
	Comments

9. Secondary Outcome

Title	Difference Between Normal and Neoplastic Tissue of p53
Description	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.
Time Frame	At time of surgery (approximately day 16)

Outcome Measure Data

Analysis Population Description

Number analyzed differs from number of participants in each arm for two reasons: sample size insufficient for analysis and sample not obtained. As well as there was not enough tissue to complete this analysis for all participants.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	13	8
Mean (Standard Deviation) [Optical Density (OD)]	-0.052 (0.185)	-0.115 (0.305)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I (Erlotinib Hydrochloride), Group II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.772
	Comments
	Method	Wilcoxon rank-sum test
	Comments

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

This analysis was not completed after discussions with DCP. Participant samples were rationed for multiple analyses, Let-7 analysis was determined to be low on the priority list and it was decided to forego this analysis.

Arm/Group Title	Group I (Erlotinib Hydrochloride)	Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.	Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
Measure Participants	0	0

Adverse Events

Time Frame	up to 9 weeks
Arm/Group Title	Group I (Erlotinib Hydrochloride)		Group II (Placebo)
Arm/Group Description	Participants receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.		Participants receive placebo PO QD on days 1, 8, and 15. Participants then undergo TURBT or cystectomy on day 16.
All Cause Mortality
	Group I (Erlotinib Hydrochloride)		Group II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/13 (0%)
Serious Adverse Events
	Group I (Erlotinib Hydrochloride)		Group II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/24 (4.2%)		2/13 (15.4%)
Gastrointestinal disorders
Lower Gastrointestinal Hemorrhage	1/24 (4.2%)	1	0/13 (0%)	0
Surgical and medical procedures
Surgical and Medical Procedures, Other	0/24 (0%)	0	2/13 (15.4%)	2
Other (Not Including Serious) Adverse Events
	Group I (Erlotinib Hydrochloride)		Group II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/24 (91.7%)		8/13 (61.5%)
Blood and lymphatic system disorders
Blood and Lymphatic System Disorders, Other	1/24 (4.2%)	1	0/13 (0%)	0
Leukocytosis	1/24 (4.2%)	1	0/13 (0%)	0
Lymph Node Pain	1/24 (4.2%)	1	0/13 (0%)	0
Ear and labyrinth disorders
Tinnitus	1/24 (4.2%)	1	0/13 (0%)	0
Endocrine disorders
Endocrine Orders, Other	1/24 (4.2%)	1	0/13 (0%)	0
Eye disorders
Dry Eye	0/24 (0%)	0	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal Pain	2/24 (8.3%)	3	0/13 (0%)	0
Bloating	1/24 (4.2%)	1	0/13 (0%)	0
Diarrhea	9/24 (37.5%)	13	1/13 (7.7%)	1
Dry Mouth	0/24 (0%)	0	1/13 (7.7%)	1
Dyspepsia	0/24 (0%)	0	1/13 (7.7%)	1
Gastroesophageal Reflux Disease	1/24 (4.2%)	2	0/13 (0%)	0
Gastrointestinal Disorders, Other	0/24 (0%)	0	1/13 (7.7%)	1
Gastrointestinal Pain	1/24 (4.2%)	1	0/13 (0%)	0
Lower Gastrointestinal Hemorrhage	1/24 (4.2%)	1	0/13 (0%)	0
Mucositis Oral	1/24 (4.2%)	1	0/13 (0%)	0
Nausea	1/24 (4.2%)	2	0/13 (0%)	0
Oral Pain	0/24 (0%)	0	1/13 (7.7%)	1
Vomiting	1/24 (4.2%)	1	0/13 (0%)	0
General disorders
Fatigue	2/24 (8.3%)	2	2/13 (15.4%)	2
Infections and infestations
Infections and Infestations, Other	1/24 (4.2%)	1	0/13 (0%)	0
Urinary Tract Infection	3/24 (12.5%)	3	0/13 (0%)	0
Injury, poisoning and procedural complications
Bruising	1/24 (4.2%)	1	0/13 (0%)	0
Investigations
Blood Bilirubin Increased	2/24 (8.3%)	2	0/13 (0%)	0
Investigations, Other	1/24 (4.2%)	1	0/13 (0%)	0
Metabolism and nutrition disorders
Anorexia	1/24 (4.2%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/24 (4.2%)	1	0/13 (0%)	0
Joint Range of Motion Decreased	1/24 (4.2%)	1	0/13 (0%)	0
Muscle Weakness Upper Limb	1/24 (4.2%)	1	0/13 (0%)	0
Musculoskeletal and Connective Tissues Disorder, Other	1/24 (4.2%)	1	0/13 (0%)	0
Pain in Extremity	1/24 (4.2%)	1	0/13 (0%)	0
Nervous system disorders
Amnesia	1/24 (4.2%)	1	0/13 (0%)	0
Cognitive Disturbance	2/24 (8.3%)	2	0/13 (0%)	0
Dizziness	2/24 (8.3%)	4	0/13 (0%)	0
Headache	2/24 (8.3%)	2	0/13 (0%)	0
Hypersomnia	1/24 (4.2%)	1	0/13 (0%)	0
Paresthesia	1/24 (4.2%)	1	0/13 (0%)	0
Tremor	1/24 (4.2%)	1	0/13 (0%)	0
Renal and urinary disorders
Bladder Spasm	2/24 (8.3%)	2	0/13 (0%)	0
Hematuria	1/24 (4.2%)	1	0/13 (0%)	0
Urinary Incontinence	1/24 (4.2%)	1	0/13 (0%)	0
Urinary Retention	3/24 (12.5%)	3	0/13 (0%)	0
Urinary Tract Pain	2/24 (8.3%)	2	0/13 (0%)	0
Urinary Urgency	0/24 (0%)	0	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Allergic Rhinitis	2/24 (8.3%)	2	0/13 (0%)	0
Aspiration	0/24 (0%)	0	1/13 (7.7%)	1
Cough	1/24 (4.2%)	1	0/13 (0%)	0
Dyspnea	1/24 (4.2%)	1	0/13 (0%)	0
Epistaxis	1/24 (4.2%)	1	0/13 (0%)	0
Nasal Congestion	1/24 (4.2%)	1	0/13 (0%)	0
Respiratory, Thoracic, and Mediastinal Disorders, Other	1/24 (4.2%)	1	0/13 (0%)	0
Sneezing	1/24 (4.2%)	1	0/13 (0%)	0
Sore Throat	2/24 (8.3%)	3	1/13 (7.7%)	1
Wheezing	1/24 (4.2%)	1	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Dry Skin	2/24 (8.3%)	2	0/13 (0%)	0
Pruritus	4/24 (16.7%)	5	0/13 (0%)	0
Rash Acneiform	6/24 (25%)	11	0/13 (0%)	0
Rash Maculo-Papular	4/24 (16.7%)	5	0/13 (0%)	0
Scalp Pain	1/24 (4.2%)	1	0/13 (0%)	0
Skin and Subcuteaneous Tissue Disorders, Other	3/24 (12.5%)	3	0/13 (0%)	0
Urticaria	2/24 (8.3%)	2	0/13 (0%)	0
Surgical and medical procedures
Surgical and Medical Procedures, Other	0/24 (0%)	0	2/13 (15.4%)	2
Vascular disorders
Flushing	1/24 (4.2%)	1	0/13 (0%)	0
Hot Flashes	1/24 (4.2%)	1	0/13 (0%)	0
Hypertension	9/24 (37.5%)	11	4/13 (30.8%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.