Conditions: Bladder Carcinoma Recurrent Bladder Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

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.

Arms:
arm 1: Patients receive erlotinib hydrochloride PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16. arm 2: Patients receive placebo PO QD on days 1, 8, and 15. Patients then undergo TURBT or cystectomy on day 16.

Interventions: intervention 1: Erlotinib Hydrochloride intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study intervention 4: Placebo intervention 5: Quality-of-Life Assessment intervention 6: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies intervention 4: Given PO intervention 5: Ancillary studies intervention 6: Undergo TURBT or cystectomy

Protocol document:
Prot_SAP_000.pdf: 
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DCP Protocol #:UWI2013-01-02                                                            UW Protocol #:    CO12336  
 
Phase II Clinical Chemoprevention Trial of Weekly Erlotinib before Bladder Cancer Surgery 
 
 
Consortium Name: 
 
 
University of Wisconsin Chemoprevention Consortium 
Name of Consortium Principal  
 
Investigator:  
 
 
Howard Bailey, MD 
 
 
 
 
 
University of Wisconsin Carbone Cancer Center 
 
 
 
 
 
600 Highland Ave. 
 
 
 
 
 
CSC K4/654 
 
 
 
 
 
Madison, WI 53792-6164 
 
 
 
 
 
Tel: (608) 263-8624 
 
 
 
 
 
Fax: (608) 265-3287 
 
 
 
 
 
hhbailey@wisc.edu 
 
Organization Name: 
 
 
University of Wisconsin Carbone Cancer Center   
Protocol Principal  
Co-Investigator: 
 
 
Tracy M Downs, MD, FACS 
 
 
 
 
 
Urology 
 
 
 
 
 
Box 3236, CSC G-5 
 
 
 
 
 
600 Highland Avenue 
 
 
 
 
 
Madison, WI 53792 
 
 
 
 
 
Tel: (608) 263-9534 
 
 
 
 
 
Fax: (608) 262-6453 
 
 
 
 
 
downs@urology.wisc.edu 
 
Organization Name:   
 
University of Rochester 
Principal Protocol 
Co-Investigator 
 
 
Edward Messing, MD 
 
 
 
 
 
601 Elmwood Avenue, Box 656 
 
 
 
 
 
Rochester NY 14642-8656 
 
 
 
 
 
Tel: (585) 275-3345 
 
 
 
 
 
Fax: (585) 442-8350 
 
 
 
 
 
edward_messing@urmc.rochester.edu 
 
Site: 
 
 
 
 
Carolina Urologic Research Center, Myrtle Beach, SC 
Investigator:  
 
 
Neal Shore, MD 
 
 
 
 
 
823 82nd Parkway, Suite B 
 
 
 
 
 
Myrtle Beach, SC 29572 
 
 
 
 
 
Tel:  (843) 839-1679 
 
 
 
 
 
Fax:  (843) 286-0119 
 
 
 
 
 
nshore@gsuro.com 
 
Site: 
 
 
 
 
Urology San Antonio Research 
Investigator: 
 
 
 
Daniel R Saltzstein, MD 
 
 
 
 
 
7909 Fredericksburg Rd. 
 
 
 
 
 
San Antonio TX 78229 
 
 
 
 
 
Tel: (210) 617-4116 
 
 
 
 
 
Fax: (210) 617-4115 


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daniel.saltzstein@urologysa.com 
 
 
 
 
 
 
 
Site:  
 
 
 
 
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
University   
Investigator:  
 
 
Trinity J. Bivalacqua, MD, PhD 
 
 
 
 
 
600 N Wolfe Street, Marburg 409 
 
 
 
 
 
Baltimore, MD 21287 
 
 
 
 
 
Tel:  (443) 287-0385 
 
 
 
 
 
Fax:  (410) 955-0833 
 
 
 
 
 
tbivala1@jhmi.edu 
 
Site: 
 
 
 
 
Lahey Clinic 
Investigator: 
 
 
 
Jason R. Gee, MD 
 
 
 
 
 
41 Mall Road 
 
 
 
 
 
Burlington, MA 01805 
 
 
 
 
 
Tel: (781) 744-8334 
 
 
 
 
 
Fax: (781) 744-5635 
 
 
 
 
 
Jason.gee@lahey.org 
 
Organization:  
 
 
University of Wisconsin 
Statistician: 
 
 
 
KyungMann Kim, PhD 
 
 
 
 
 
University of Wisconsin 
 
 
 
 
 
600 Highland Ave, CSC K6/438 
 
 
 
 
 
Madison, WI 53792 
 
 
 
 
 
Tel: (608) 265-6380 
 
 
 
 
 
Fax: (608) 265-5579 
 
 
 
 
 
kmkim@biostat.wisc.edu 
 
 
 
 
 
 
Organization:  
 
      University of Wisconsin 
Erlotinib Consultant:  
 
Anne Traynor, MD 
 
 
 
 
 
University of Wisconsin 
 
 
 
 
 
3103 WI Institute Medical Research 
 
 
 
 
 
1111 Highland Ave 
 
 
 
 
 
Madison, WI 53792 
 
 
 
 
 
Tel: (608) 262- 5092 
 
 
 
 
 
amt@medicine.wisc.edu 


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IND Sponsor:  
Division of Cancer Prevention 
 
 
 
 
 
 
 
National Cancer Institute, NIH, DHHS 
 
 
 
Shady Grove Campus 
 
 
 
9609 Medical Center Dr., Suite 5E-536 
 
 
 
Rockville, MD  20850 (For FedEx, use Rockville, MD  20852) 
 
 
 
(240) 276-7094 
 
IND# 
 
 
64808 
 
Agent(s)/Supplier: 
Division of Cancer Prevention 
 
NCI Contract # 
HHSN261201200033I 
 
Protocol Version Date: 06-28-2017 
 
Protocol Revision or  
 
Amendment #  
Version 10 
 
 


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SCHEMA 
 
Phase II Clinical Chemoprevention Trial of Weekly Erlotinib before 
Bladder Cancer Surgery 
 
Male and Female participants who have a bladder tumor, confirmed by cystoscopy, 
are candidates for TURBT or cystectomy with a calculated Creatinine clearance (Cockcroft Gault) of ≥ 30 
mL/min and normal liver function, 18 years and older, and Karnofsky Performance Status (KPS) of ≥ 
60%. 
 
Baseline safety assessments, plasmapharmacokinetics, I-PSS evaluation. 
 
Participants will be randomized on a 1:2 ratio to placebo vs erlotinib with stratification for planned use of 
agents which significantly decrease erlotinib bioavailability and by planned surgery (TURBT vs. 
cystectomy) 
Placebo 4 tablets weekly for 3 doses  
Erlotinib 4 tablets (150 mg tablets=total dose 600 
mg) weekly for 3 doses  
 
Weekly for 3 doses preceding bladder surgery* 
(*If the planned day 16 surgery is going to be delayed to either day 17-22 the day 15 dose should be held 
and administered on the evening prior to the new surgery date; if the planned day 16 surgery is delayed to 
day 23-28 the day 15 dose should be administered as planned and a 4th dose administered on the evening 
prior to the new surgery date.  If surgery is delayed further than 28 days (4 weekly doses) the participant 
will be considered not evaluable for the primary endpoint.) 
 
Day 8 Visit* 
Day 8 safety assessments, plasma pharmacokinetics 
(*Day 8 clinic visit will be optional; there will be a required phone contact for safety assessment) 
 
 
The day after the third dose (Day 15 dose or, for surgical delays beyond  
the 16th day but less than the 23rd day) 
or 
The day after the fourth dose of study medication for surgery delayed to day 23 – day 28 
 
End-of-study safety assessments, plasma pharmacokinetics, I-PSS evaluation, 
TURBT or Cystectomy, tissue biomarkers. 
 
Primary Endpoint 
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 
weekly as compared to placebo. 
 
Secondary Endpoints 


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Assess the tolerance of high dose weekly erlotinib compared to placebo; assess limited pharmacokinetics 
of weekly erlotinib; and assess the expression of EGFR, e-cadherin, Ki67, ERK, p53 and let-7 in normal 
and abnormal urothelium, exploratory assessment of urination symptoms in men. 


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TABLE OF CONTENTS 
 
 
COVER PAGE.............................................................................................................................................. 1 
 
SCHEMA ...................................................................................................................................................... 4 
1. 
OBJECTIVES .................................................................................................................................. 9 
1.1 
Primary Objectives........................................................................................................................... 9 
1.2 
Secondary Objectives....................................................................................................................... 9 
 
2. 
BACKGROUND ............................................................................................................................. 9 
2.1 
Bladder Cancer ................................................................................................................................ 9 
2.2 
Erlotinib ......................................................................................................................................... 11 
2.3 
Rationale ........................................................................................................................................ 12 
 
3. 
SUMMARY OF STUDY PLAN ................................................................................................... 14 
 
4. 
PARTICIPANT SELECTION ....................................................................................................... 16 
4.1 
Inclusion Criteria ........................................................................................................................... 16 
4.2 
Exclusion Criteria .......................................................................................................................... 17 
4.3 
Inclusion of Women and Minorities .............................................................................................. 19 
4.4 
Recruitment and Retention Plan .................................................................................................... 19 
 
5. 
AGENT ADMINISTRATION ...................................................................................................... 20 
5.1 
Dose Regimen and Dose Groups ................................................................................................... 20 
5.2 
Erlotinib Administration ................................................................................................................ 20 
5.3 
Run-in Procedures .......................................................................................................................... 21 
5.4 
Contraindications ........................................................................................................................... 21 
5.5 
Concomitant Medications .............................................................................................................. 21 
5.6 
Dose Modification ......................................................................................................................... 22 
5.7 
Adherence/Compliance .................................................................................................................. 22 
 
6. 
PHARMACEUTICAL INFORMATION ...................................................................................... 22 
6.1 
Study Agent ................................................................................................................................... 22 
6.2 
Reported Adverse Events and Potential Risks ............................................................................... 23 
6.3  
Availability .................................................................................................................................... 26 
6.4 
Agent Distribution ......................................................................................................................... 26 
6.5  
Agent Accountability ..................................................................................................................... 26 
6.6 
Packaging and Labeling ................................................................................................................. 27 
6.7 
Storage ........................................................................................................................................... 27 
6.8 
Registration/Randomization .......................................................................................................... 27 
6.9 
Blinding and Unblinding Methods ................................................................................................. 28 
6.10 
Agent Destruction/Disposal ........................................................................................................... 28 
 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ................................................................... 30 
7.1 
Schedule of Events ......................................................................................................................... 30 
7.2 
Baseline Testing/Prestudy Evaluation ......................................................................................... 301 
7.3 
Evaluation During Study Intervention ........................................................................................... 32 
7.4 
Evaluation at Completion of Study Intervention ........................................................................... 33 
7.5 
Post-intervention Follow-up Period ............................................................................................... 33 


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7.6 
Methods for Clinical Procedures ................................................................................................... 34 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION ........................................... 34 
8.1 
Primary Endpoint ........................................................................................................................... 34 
8.2 
Secondary Endpoints ..................................................................................................................... 34 
8.3 
Off-Agent Criteria .......................................................................................................................... 36 
8.4 
Off-Study Criteria .......................................................................................................................... 37 
8.5 
Study Termination ......................................................................................................................... 37 
 
9. 
CORRELATIVE/SPECIAL STUDIES ......................................................................................... 37 
9.1 
Rationale for Methodology Selection ............................................................................................ 37 
9.2 
Comparable Methods ..................................................................................................................... 40 
 
10. 
SPECIMEN MANAGEMENT ...................................................................................................... 40 
10.1 
Laboratories ................................................................................................................................... 40 
10.2 
Collection and Handling Procedures ............................................................................................. 40 
10.3 
Shipping Instructions ..................................................................................................................... 41 
10.4 
Tissue Banking .............................................................................................................................. 41 
 
11. 
REPORTING ADVERSE EVENTS ............................................................................................. 41 
11.1 
Adverse Events .............................................................................................................................. 42 
11.2 
Serious Adverse Events ................................................................................................................. 44 
 
12. 
STUDY MONITORING ............................................................................................................... 45 
12.1 
Data Management .......................................................................................................................... 45 
12.2 
Case Report Forms ......................................................................................................................... 45 
12.3 
Source Documents ......................................................................................................................... 45 
12.4 
Data and Safety Monitoring Plan ................................................................................................... 46 
12.5 
Sponsor or FDA Monitoring .......................................................................................................... 46 
12.6 
Record Retention ........................................................................................................................... 46 
12.7 
Cooperative Research and Development Agreement(CRADA)/Clinical Trials Agreement(CTA)46 
 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................... 47 
13.1 
Study Design/Description .............................................................................................................. 47 
13.2 
Randomization/Stratification ......................................................................................................... 48 
13.3 
Sample Size and Feasibility ........................................................................................................... 48 
13.4 
Primary Objective, Endpoint(s), Analysis Plan ............................................................................. 48 
13.5 
Secondary Objectives, Endpoints, Analysis Plans ......................................................................... 49 
13.6 
Reporting and Exclusions .............................................................................................................. 49 
13.7 
Evaluation of Toxicity ................................................................................................................... 49 
13.8 
Evaluation of Outcomes/Endpoints ............................................................................................... 50 
13.9 
Interim Analysis ............................................................................................................................. 50 
13.10 Ancillary Studies ............................................................................................................................ 50 
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................. 50 
14.1 
Form FDA 1572 ............................................................................................................................. 50 
14.2 
Other Required Documents ............................................................................................................ 50 
14.3 
Institutional Review Board Approval ............................................................................................ 51 
14.4 
Informed Consent .......................................................................................................................... 51 
14.5 
Submission of Regulatory Documents…………………………………………………………... 51 


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14.6 
Other .............................................................................................................................................. 52 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ................................................................... 52 
 
REFERENCES ........................................................................................................................................... 53 
 
APPENDIX A……………………………………………………………………………………………..61 
 
APPENDIX B……………………………………………………………………………………………..62 
 
APPENDIX C……………………………………………………………………………………………..64 
 
CHEMOPREVENTION INFORMED CONSENT …………………………………………..………….66


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1. 
OBJECTIVES 
 
1.1 
Primary Objectives – 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 weekly as compared to placebo.    
 
1.2 
Secondary Objectives –  
 
- 
Assess the tolerance of high dose weekly erlotinib compared to placebo 
- 
Assess the expression of phosphorylated EGF receptor in tumor tissue when available 
- 
Assess the expression of e-cadherin and Ki67 in normal and abnormal urothelium 
- 
Assess the expression of phosphorylated ERK in normal and abnormal urothelium 
- 
Assess limited pharmacokinetics of weekly erlotinib 
- 
Assess the expression of p53 in normal and abnormal urothelium 
- 
Assess the expression of  let-7 in normal and abnormal urothelium 
- 
Exploratory assessment of urination symptoms in men 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
Bladder cancer is the second most common malignancy of the genitourinary tract. During the year 2012 
alone, approximately 73,510 new cases will be diagnosed with an estimated 14,880 deaths occurring in 
the United States as a result of this disease (Siegel 2012). Urothelial carcinoma of the bladder may present 
as either superficial cancer or muscle-invasive cancer, which is associated with considerable morbidity 
and mortality. Muscle-invasive bladder cancer, a major source of morbidity and mortality, is initially 
diagnosed in as many as 30% of patients. These patients generally undergo radical cystectomy, and often 
neoadjuvant or adjuvant chemotherapy, for locally advanced disease. However, the remaining 70% of 
patients with bladder cancer are initially diagnosed with superficial bladder tumors. Superficial bladder 
cancer is often characterized by multifocal and recurrent disease that may appear anywhere in the bladder 
over relatively long intervals, thereby requiring long-term surveillance (Raghavan 1990; Gee 2002). 
Superficial bladder cancer includes non-invasive papillary tumors (Ta), carcinoma in situ (CIS/Tis), and 
tumors that invade through the lamina propria (T1). Patients diagnosed with superficial tumors are usually 
reevaluated at frequent intervals to detect recurrent disease (Forseman and Messing 1997). Repeated 
examination entails regular cystoscopic evaluation and monitoring of urine cytology and/or other 
diagnostic markers. As such, this closely monitored group of patients at risk for tumor recurrence and 
progression represents an ideal cohort for the evaluation of chemopreventive agents. 
 
In general, 30%–80% of people with superficial bladder cancer will develop recurrent tumors (Bono 
1994). A higher risk of tumor recurrence is associated with multifocal disease observed at the time of 
initial diagnosis, high tumor grade, depth of invasion, and cystoscopic findings 3 months after diagnosis. 
It has been reported that 70% of patients with multiple bladder tumors will have recurrent disease by one 
year, whereas approximately 50% of patients diagnosed with a solitary bladder tumor will experience 
disease recurrence by 4 years. Up to 10% of recurrent bladder tumors progress to muscle-invasive 
disease. The risk of tumor progression is lowest for individuals with stage Ta papillary tumors in that only 
4% of individuals with Ta tumors will progress to muscle-invasive disease as compared with a 30% 
progression rate for T1 tumors within 3 years (Grossman 1996).  
 
Bladder cancer is thought to evolve along one of two phenotypic pathways: superficial (papillary) or 
invasive (Koss 1992). These pathways are characterized by specific genetic defects. The 


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superficial/papillary pathway genotype is characterized by alterations in chromosome alleles 9p and 9q, 
while the CIS/invasive pathway is characterized by dysfunction of p53 or pRb (Dalbagni 1993; Rosin 
1995; Spruck 1994; Wagner 1995). It is unlikely that these specific genetic derangements alone are 
sufficient to trigger malignant transformation of normal cells, suggesting that other genetic events or 
environmental exposure may contribute to their malignant potential as well.  
 
Epidermal growth factor receptor (EGFR) is synthesized from a 1210-residue polypeptide precursor, after 
cleavage of the N-terminal sequence, an 1186-residue protein is inserted into the cell membrane (Jim 
2006). Over 20% of the receptor is N-linked glycosylation and this is required for translocation of the 
EGFR to the cell surface and subsequent acquisition of function (Slieker 1986). EGFR is a 170-kDa 
transmembrane protein that is a member of a family of related receptor protein tyrosine kinases (PTKs) 
that also includes the proteins encoded by the c-erbB-2 (neu), c-erbB-3, and c-erbB-4 genes (Kumar 
1995). The EGFR receptor regulates the intracellular effects of ligands such as EGF and transforming 
growth factor α (TGF α). (Carpenter 1990, Wells 1999, Yarden 2001). Upon ligand binding to the EGFR 
extracellular domain (collectively called the ectodomain), there is an increase in the proportion of 
dimerized receptor and the enzymatic activity of its intracellular tyrosine kinase domain increases greatly 
(Cohen 1982, Yarden 1987).  
 
The EGFR kinase catalyses the transfer of the ϒ-phosphate of bound ATP to the tyrosine residues of 
exogenous substrates and the C-terminal domains of the EGFR (Powis & Workman 1994, Kumar 1995). 
The EGFR also interacts with its three known homologues, ErbB2 (also called Neu or HER2), ErbB3 
(HER 3), and ErbB4 (HER4), in a ligand-dependent fashion to form heterodimers (Yarden 2001, 
Olayloye 2000) The sequence identity of the EGFR family varies from 37% (53% similarity) for EGFR 
and ErbB3 to 49% (64% similarity) for the EGFR and ErbB2.  
 
Activation of EGFR can occur via autocrine, paracrine or juxtacrine mechanisms. On ligand binding, 
EGFR dimerizes with neighboring receptors and is autophosphorylated at three major tyrosine residues 
(Chinni 2003). EGFR, subsequently interacts signaling transduction pathways, including phospholipase C 
ϒ, phosphatidylinositol-3’-kinase, growth factor receptor-binding protein 2 (Grb-2), Src family kinases, 
and components of the Jak/STAT pathway (Kim 2009, Sliva 2008). Deregulated expression of EGFR and 
its ligands has been associated with the development of neoplasia in both animals and humans. At 
physiological receptor levels, EGF binding results in phosphorylation of Src homology 2 domain-
containing proteins, which is sufficient to induce a normal mitogenic response (Kelloff 1996). In addition, 
an increase in EGFR expression, other substrates such as phospholipase C ϒ, and Ras-GAP, become 
phosphorylated. This might explain in part, how EGFR overexpression contributes to carcinogenesis.  
 
Two general patterns have been recognized in aberrant EGFR-mediated signal transduction. The first 
pattern is a trend toward increased expression of EGFR during the early stages of carcinogenesis followed 
by receptor down-regulation, often subsequent to increased ligand production. This pattern has been 
observed for example in the lung, cervix and prostate. The second recurring pattern observed is the 
expansion of receptor and/or ligand expression from a subset of cells in normal tissue (usually in the basal 
layer) to extended cellular layers during neoplastic progression. This pattern has been observed in head 
and neck, bladder and cervix. 
 
Lubet et al. (Lubet 2010) using an in vivo bladder cancer model analyzed three different agents to 
determine the optimal agents to consider studying in clinical prevention trials. Using Harlan rat model 
animals were treated with naproxen (400mg/kg diet), aspirin (low dose – 300mg/kg diet, high dose – 
3,000 mg/kg diet), Iressa® (10mg/kg gefitinib body weight daily) or resveratrol (1,000mg/kg diet) using 
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cancer and continued for 7 months, Protocol 2, drug administration 3 months after chemically induced 
bladder cancer with microscopic lesions visible and agent continued for 3 months and Protocol 3 (drug 
administered one week after chemically induced bladder cancer- OH-BBN and drug continued for 4 
months. In animals treated under protocol number 1 naproxen, Iressa, and both doses of aspirin decreased 
the formation of large bladder tumors by 87% 90% 6% and 60% respectively. Tumors increased in size 
by 3% for animals treated with resveratrol. In protocol 2, both Iressa and naproxen were both highly 
effective and in protocol 3 only Iressa caused a significant decrease in microscopic bladder cancers 
(63%). The investigators concluded that the two most promising agents in this study were naproxen and 
gefitinib/Iressa. Gefitinib/Iressa was effective both in preventing large tumor formation plus effective 
when administered after microscopic lesions were already established in the bladder. It seems plausible 
based on this research that EGFR inhibitors (erlotinib) should be explored for bladder cancer prevention 
either as monotherapy or a combinatorial approach. Data with gefitinib and erlotinib strongly imply that 
small molecule inhibitors of EGFR have the potential to be effective bladder cancer preventive agents 
therefore we propose to test erlotinib. 
 
2.2 
Study Agent 
 
Erlotinib HCl (Tarceva) is an orally available, highly selective, reversible inhibitor of epidermal growth 
factor receptor (HER1/EGFR) tyrosine kinase. Inhibition of tyrosine kinase activity prevents 
HER1/EGFR phosphorylation, the associated downstream signaling events, and may block tumorigenesis 
mediated by inappropriate HER1/EGFR signaling. Erlotinib inhibits the intracellular phosphorylation of 
tyrosine kinase associated with the EGFR. The recommended dosing in adults is a daily oral dose of 150 
mg continuously or until dose-limiting toxicity leads to an interruption and possible reduction in daily 
dosing.  
 
Erlotinib pharmacokinetic analyses have been characterized by the following observations; a relatively 
long half-life (10-12 hours), predominant metabolism via P450 metabolism with some correlation to 
hepatic function, and increasing AUC values with repeated daily dosing (White-Koning 2011, Hamilton 
2006). Also multiple studies have correlated an increasing AUC of erlotinib or gefitinib with the 
occurrence of skin toxicity (White-Koning 2011, Thomas 2009) while there are other studies, which have 
not confirmed this association (Calvo 2007). Current smokers have been observed to tolerate erlotinib and 
gefitinib better than non-smokers but also to have less benefit observed. Consistent with these 
observations Hamilton et al (Hamilton 2006) performed a comparison pharmacokinetic study of erlotinib 
in current smokers and non-smokers at doses of 150 and 300 mg. They observed that current smokers had 
AUC and Cmax values approximately half of non-smokers or smokers at 300 mg had AUC values similar 
to non-smokers at 150 mg daily. It is theorized the likely explanation of this is the known contribution of 
CYP1A1 and CYP1A2 to the metabolism of erlotinib and their induction by cigarette smoking. 
 
Over 50 Astellas (formerly OSI Pharmaceuticals, Inc.)-sponsored phase 1, 2, and 3 clinical studies of 
erlotinib have been initiated or completed. Various doses and schedules of erlotinib as a single agent and 
in combination with conventional chemotherapy agents have been studied. Twelve phase 1 studies have 
been conducted in healthy volunteers to determine the safety, tolerance, pharmacology, and 
pharmacokinetics of erlotinib (n = 268). The phase 1 healthy subject experience is based on the use of 
different oral erlotinib doses and schedules ranging from single-dose administration of 1–1000 mg to 
administration of 200 mg twice daily (bid) compared with placebo. Early tolerability studies showed that 
200 mg erlotinib bid was associated with dose-limiting rash and diarrhea in addition to reversible liver 
transaminase elevation. Subsequent single- or multiple-dose pharmacology studies of 100 or 150 mg 
erlotinib daily did not reveal any new safety findings; however, the characteristic acneiform rash was 
unacceptable in healthy subjects receiving 150 mg erlotinib daily for approximately 1 week or longer. The 
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maximum tolerable dose (MTD) of single-agent erlotinib was determined to be 150 mg daily, with 
diarrhea being the dose-limiting toxicity (DLT) despite supportive antidiarrheal treatment. Weekly dosing 
of erlotinib up to 1600 mg did not define an MTD; however, severe drug-related skin disorders were 
reported for patients receiving 1400 and 1600 mg weekly.  
 
There is limited published data with weekly erlotinib which has been tried as a delivery schedule to 
potentially lessen the toxicity observed with daily erlotinib. Grommes et al (Grommes 2011) retrospective 
assessed 9 lung cancer patients with brain metastases treated with weekly erlotinib (900 - 1500 mg).  Two 
patients developed grade 1-2 rash and fatigue.  Of note, all had prior daily treatment with erlotinib or 
gefitinib potentially leading to selection bias and it is possible concomitant steroids and anti-seizure 
medications could alter erlotinib metabolism. Sangha et al. (Sangha 2011) performed a phase 1/2 dose 
escalation trial of weekly or daily erlotinib with docetaxel in lung cancer patients. Arm A (weekly 
erlotinib) patients were started at 1200 mg of Erlotinib weekly for 3 doses with concomitant docetaxel. 
Due to significant neutropenia/infection the maximum tolerable dose was considered 600 mg of Erlotinib 
(weekly) and 70 mg/m2 docetaxel; but this regimen was not considered clinically viable. No grade 3/4 
skin toxicities were reported but they did not detail the incidence of grade 1-2 skin toxicity for arm A, 
other than to imply it was common (>70%). Milton et al. (Milton 2006) performed a dose-escalation 
study in advanced lung cancer patients. Fourteen patients received doses of 1200, 1600 and 2000 mg 
weekly. Rash and diarrhea were the most frequent toxicities. Eleven of 12 evaluable Phase I patients 
experienced Grade 1 or 2 rash. The rash generally persisted but improved with continued weekly dosing. 
Of the 5 patients who developed Grade 2 rash in the Phase I portion of the trial, most did so within 2 
weeks of starting erlotinib. The rash lasted 1 or 2 weeks in 3 patients and >4 weeks in 2 patients. These 5 
patients were given topical clindamycin and/or oral minocycline. Similarly, 11 of 12 patients experienced 
Grade 1 or 2 diarrhea. Diarrhea generally was experienced within 24 to 48 hours of drug administration 
and was controlled well with loperamide therapy given on an as-needed basis.  Thirteen additional 
patients were enrolled at 2000 mg weekly, again the vast majority experienced grade 1-2 rash and 
diarrhea.  Grade 2 rash with weekly erlotinib was more frequent numerically with dose escalation and 
developed in 42% of patients who received 2000 mg and in 17% of patients who received 1200 mg or 
1600 mg. The frequency of Grade 2 diarrhea was 26% in the 2000-mg weekly group and 33% in the 
1200-mg weekly and 1600-mg weekly groups.  Of 6 patients at 1200 and 1600 mg dose levels, all six 
developed at least grade 1 rash or diarrhea.   
 
2.3 
Rationale 
 
The strategy of targeting specific PTKs such as EGFR seems plausible due to the redundancy of growth 
factor networks and EGFR is overexpressed in a subset of cancers (bladder, breast, cervix, colon, 
esophagus, lung, prostate, and head and neck). The development of novel therapies remains an area of 
unmet need in the treatment of both superficial and muscle invasive bladder cancer. One of the most 
important targets for chemo-preventive intervention and drug development are deregulated signal 
transduction pathways (Kelloff 1996). Key components of these pathways are the protein tyrosine kinases 
(PTKs), which catalyze the transfer of the γ-phosphate of ATP to the hydroxyl group of tyrosine on 
numerous proteins (Chang 1992). Loss of PTK regulatory mechanism has been implicated in neoplastic 
growth and numerous oncogene codes for PTKs (Powis 1994, Powis and Workman 1994). The strategy 
of targeting specific PTKs such as EGFR seems plausible due to the redundancy of growth factor 
networks and EGFR is overexpressed in a subset of cancers (bladder, breast, cervix, colon, esophagus, 
lung, prostate, and head and neck).  
 
In bladder cancer, EGFR/ERBB2 is frequently overexpressed (> 75% of transitional cell carcinomas) and 
the level of overexpression has been directly correlated with tumor grade/stage, tumor recurrence and 
overall survival (Neal 1990, Messing 1990, Mellon 1995, Chow 2001). Experimental evidence in bladder 


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cancer has also suggested that the EGFR pathway plays a critical role in cell proliferation, apoptosis, 
differentiation, migration and angiogenesis (Bellmunt 2003, Black 2007, MacLaine 2008). The 
distribution of EGFR differs between normal and neoplastic urothelium. For example, Messing and 
Reznikoff (Messing and Reznikoff 1992) noted in the normal bladder EGFR is only expressed on cells of 
the basal layer, whereas in malignant or dysplastic urothelium, along with histologically normal 
urothelium from bladder cancer patients, EGFR is equally expressed on cells of the urothelial layers, 
including those directly in contact with urine. In bladder cancer patients, the percentage of EGFR-
expressing cells is lowest in tissue distant from the tumor, but increases in tissue adjacent to the tumor 
and is highest in the tumorous tissue (Rao 1993). Superficial bladder cancers (pTa, pT1, pTis/pCis) that 
express EGFR are significantly more likely to progress toward muscle invasive disease (Neal 1990). 
Because high levels of EGF are excreted in the urine, expression of EGFR in the premalignant and 
malignant bladder transitional epithelium could have a significant impact on proliferation of these cells 
(Messing and Reznikoff 1992). 
 
Chaux et al. demonstrated EGFR protein overexpression to occur in 74% of urothelial carcinomas of the 
bladder (Chaux 2012). Fifty percent of tumors had high levels of EGFR, 22% low levels of EGFR and 
28% of tumors were negative for EGFR. In the adjacent urothelium, 22% low levels of EGFR and 78% 
were negative for EGFR (Chaux 2012). The protein overexpression of EGFR has not been shown to be 
associated with mutations within tyrosine kinase domains (exons 19 and 21) of the EGFR gene (Chaux 
2012). With the exception of non-small cell carcinomas and glioblastomas, the overall prevalence of 
EGFR activating mutations in solid malignancies is very low. To date, neither gene amplification nor 
point mutations of EGFR have been reported in bladder tumors (Blehm 2006).   
 
Although mutations in the coding region of EGFR are rare, in invasive bladder tumors, differential 
sensitivity to erlotinib was recorded by Jacobs et al. (Jacobs 2007) in a panel of cell lines in the absence 
of EGFR mutations. Jacobs and colleagues analyzed DNA from 112 invasive bladder tumors, 
investigating exons 18-21, which represent the catalytic domain of the receptor. Five point mutations 
(A839T, A859T, A864Q, Y869C and K875R) were identified (Jacobs 2007). All mutations found were 
located within exon 21 of the EGFR gene. No mutations were found in exons 18-20 of the EGFR gene. 
Cell lines whose sensitivity profile to erlotinib was established were included in their study. Loss of pAKt 
was most significant in bladder cancer cell lines sensitive to erlotinib (cell line 5637), moderate decrease 
in moderately sensitive cell lines (CUBIII) and no decrease in pAkt in two erlotinib insensitive cell lines 
(UM-UC-3 and J82). Epthelial-mesenchymal transition (EMT) has been linked as a phenotypic indicator 
of sensitivity to erlotinib (Thomson 2005 ref21). The EMT phenotype linked to decrease drug sensitivity 
included loss of E-cadherin expression with concomitant expression of vimentin and fibronectin. Jacobs 
et al. reported the epithelial-mesenchymal transition (EMT) in erlotinib insensitive cells lines (MGHU1, 
TCCSUP, UM-UC3, J82) (Jacobs 2007). In bladder cancer cell lines sensitive to erlotinib, the 
phosphorylation status of Akt is primarily regulated via the EGFR signaling pathway. In cell lines 
insensitive to erlotinib, uncoupling of the EGFR signaling pathways has been reported with different 
levels of Akt phosphorylation suggesting the role of other molecular events such as H-ras mutations, and 
loss of PTEN function. The investigators concluded that even in the absence of EGFR mutations erlotinib 
shows potential as a therapeutic agent for bladder cancer to decrease neoplastic progression. Molecular 
hallmarks of erlotinib insensitivity include EMT and phosphorylation status of Akt.  
 
In a phase II clinical trial erlotinib (Pruthi 2010) was given neoadjuvantly (150mg once daily for 4 weeks) 
in 20 patients with clinical stage T2 disease prior to undergoing radical cystectomy. The primary endpoint 
of this phase II trial was to determine the effect of neoadjuvant erlotinib before cystectomy on the 
pathological complete response rate (pT0 rate) in cystectomy specimens. Of the 20 patients receiving 
erlotinib neoadjuvantly, 15 developed grade 1 to 3 (4 subjects with grade 3) skin toxicity during the 28 
day schedule. Five had their dose reduced or held because of skin toxicity.  Results of operative pathology 


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showed that five (25%) of 20 patients had a complete response (pT0) at the time of cystectomy, and in 
total seven (35%) had pathologic down staging at the time of cystectomy. Interestingly, all pT0 and 
pTis/T1 patients had a rash.   
 
EGFR transcript in peripheral blood has been proposed as a marker for circulating bladder cancer cell 
detection (Sun 2011). Antoniewicz and colleagues (Antoniewicz 2012) analyzed 51 patients who 
underwent transurethral resection of bladder tumor (TURBT) to determine if circulating urothelial cells in 
the peripheral blood increased after TURBT. While none of the 4 studied genes using RT-PCR 
demonstrated any significant increase in the number of PCR-positive transcripts after TURBT, only 
EGFR was significantly less frequent 30 days following surgery compared to results obtained prior to 
surgery (Antoniewicz 2012). At baseline the percent of positive RT-PCR signal for EFGR was 27% and 
decreased to 20%, 14%, 10% and 4% on postoperative days 1, 3, 7 and 30 respectively.  
 
Actin remodeling has been proposed as a marker of malignant-associated field defect and a potential 
surrogate biomarker for chemoprevention trials. Erlotinib testing in a bladder carcinogenic model 
consisting of untransformed HUC-PC cells and transformed MC-T11 cells, both derived from the same 
normal human urothelial clone immortalized by SV40. At higher doses, erlotinib induced a decrease in 
cell adhesion and anoikis (detachment-associated apoptosis). This inhibitory effect was not seen with a 
MAPK (P44/P42) inhibitor suggesting that other pathways may be responsible for erlotinib induced actin 
remodeling (Jin 2006 ref22). CD34+ fibrocytes are constitutive elements of the connective tissue and play 
a role in matrix synthesis and tumor associated stromal remodeling. Secreted protein, acidic and rich in 
cysteine (SPARC) is a pivotal mediator of stromal remodeling precipitated by invasive carcinomas. In 
contrast to the tumor free urinary bladder, including chronic cystitis, invasive urothelial carcinomas reveal 
complete loss of CD34+ fibrocytes in the lamina propria, increased expression of SPARC and the 
appearance of alpha-smooth muscle actin (α-SMA) myofibroblasts in the superficial lamina propria 
(Nimphius 2007). 
 
In addition to the concept of EGFR antagonism as a target for bladder cancer prevention, another topic we 
plan to explore is the concept of intermittent dosing for prevention.  More often than not, this concept is 
pursued for patient compliance or tolerance issues. A current example in preventive health is the use of 
bisphosphonates (e.g. Fosamax) for prevention of osteoporosis and its complications. Fosamax is 
approved as a daily oral agent, but toxicity and tolerance has led to many clinicians prescribing it weekly 
rather than daily (Lee 2011). Intermittent dosing for cancer prevention has also been proposed and 
explored in animal models with supporting data (Lubet 2008, Lubet 2013 unpublished). As described 
above there are supporting data from lung cancer therapy studies that weekly erlotinib could achieve 
equal or greater dose intensity (as compared to daily) with less skin and GI toxicity (Milton 2006). 
 
3. 
SUMMARY OF STUDY PLAN 
 
Protocol chairperson: Tracy M. Downs, MD FACS, University of Wisconsin 
 
Primary Endpoint: The primary objective is 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 weekly as compared to placebo.   
  
The prioritized secondary objectives are:  1) to assess the tolerance of high dose weekly erlotinib 
compared to placebo. 2) to assess the expression of phosphorylated EGFR in tumor tissue when available. 
3) to assess the expression of e-cadherin and Ki67 in normal and abnormal urothelium. 4) to assess the 
expression of phosphorylated ERK in normal and abnormal urothelium. 5) to assess limited 


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pharmacokinetics of weekly erlotinib. 6) to assess the expression of p53 in normal and abnormal 
urothelium. 7) to assess the expression of  let-7 in normal and abnormal urothelium.  8) perform an 
exploratory assessment of men on whether urination symptoms alter while on study. 
 
Study Schema: 
 
This is a multi-center, phase IIa randomized, double-blind, placebo-controlled study.  Participants will be 
randomized on a 1:2 ratio to placebo vs. active study agent and stratified according to planned surgery 
(TURBT vs. cystectomy) and use of agents that significantly decrease Erlotinib bioavailabiltity (tobacco, 
protein pump inhibitors).  Fifteen participants will be enrolled on the placebo arm.  A maximum of 30 
participants will be enrolled on the active intervention arm. The accrual goals account for an anticipated 
dropout rate of 5-10%.  Total anticipated accrual is therefore 45 participants.  
 
There will be six sites participating in the study.  Each randomized patient will be treated with study 
medication weekly x 3 doses.  We will allow for study duration of approximately 3 years. 
 
• 
Placebo or 
• 
Erlotinib (with allowance for a 50% dose reduction for adverse events as specified in section 5.6) 
 
Participants for this protocol will be accrued from a population of males and females 18 years of age and 
older who have a confirmed or suspected bladder tumor which will be treated with TURBT (or planned 
cystoscopy with biopsies) or cystectomy (total or partial).  Eligible participants will be randomly assigned 
to either 600 mg erlotinib PO or matching placebo once weekly for 3 doses preceding their scheduled 
bladder surgery.  The study will be terminated when all participants have completed study dosing, their 
scheduled surgical treatment, and a 7-14 day post-surgery follow-up period. 
 
There is no run-in period specified for this protocol.  Potential study participants will be identified from 
the population of patients being evaluated and treated for bladder tumors at each of the participating 
institutions.  After being presented with information about the protocol, patients interested in participating 
will be scheduled for a screening/baseline study visit.  After completion of the informed consent process, 
the following assessments/procedures will be conducted: 
 
 
 
Screening/Baseline visit (within 30 days of first dose of study agent):  
o eligibility assessment 
o medical/surgical history and baseline symptoms 
o physical exam/vital signs (including performance status assessment) 
o clinical safety labs (including pregnancy testing for females of childbearing potential) 
o plasma pharmacokinetics 
o request for randomization 
o International Prostate Symptom Score (I-PSS) 
 
Study agent and topical ointment (topical clindamycin, topical hydrocortisone) dispensing: 
(within 30 days of baseline assessments) either in clinic or study agent will be mailed to the 
participant via overnight courier with a phone contact prior to dosing.  Ointment instructions will 
be included (See Appendix B). 
o study agent dosing instructions 
o ointment instructions 
o concomitant medication review and adverse event assessment 
 


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Pre Day 8 Phone contact (approximately 24-72 hours prior to Day 8 Visit):  
o instruct participant on dose and time of Day 8 study drug administration 
 
 
Day 8 Visit*:  
o physical exam/vital signs (including complete assessment of any rash per CTCAE 
criteria) 
o clinical safety labs 
o plasma pharmacokinetics 
o Day 8 Study dosing after plasma pharmacokinetics 
o concomitant medication review, compliance and adverse event assessment 
*The day 8 clinic visit will be optional; if the participant opts out then a post day 8 phone contact (within 48 hours of 
taking dose) will be required for a concomitant medication review, compliance and adverse event assessment. 
 
 
 
Pre-Surgery reminder Phone contact (approximately 24-72 hours prior to Surgery):  
o instruct participant on dose and time of pre-surgical study drug administration 
 
 
Surgery visit: (Day 15-16): 
o physical exam/vital signs 
o clinical safety labs 
o plasma pharmacokinetics 
o concomitant medication review, compliance and adverse event assessment 
o International Prostate Symptom Score (I-PSS) 
o collection of paraffin-embedded blocks or slides after standard pathology processing  
 
Post-Surgery phone contact (7-14 days post-surgery): 
o concomitant medication review and adverse event assessment 
 
Duration of study participation will range from 29-56 days depending upon how long before the 
day 1 study agent dosing occurs after the screening/baseline assessments. 
 
 
4. 
PARTICIPANT SELECTION 
 
4.1 
Inclusion Criteria 
 
4.1.1  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. 
 
4.1.1.1 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: 
 
1) calculated creatinine clearance of < 60 ml/min 
 
2) KPS < 80 
 
3) solitary kidney or 
 
4) patient refusal to undergo neoadjuvant chemotherapy. 
 
4.1.2 
 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 
 


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4.1.3 
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. 
 
4.1.4  Age ≥18 years. Because no dosing or adverse event data are currently available on 
the use of high dose weekly erlotinib in patients less than 18 years of age, children are excluded from 
this study but will be eligible for future pediatric trials, if applicable. 
 
4.1.5  Karnofsky ≥60%; see Appendix A 
 
4.1.6  Participants must have normal * organ and marrow function as defined below: 
 
 
4.1.6.1 Hematologic: 
 
WBC ≥ 3000/mm3; 
 
platelets ≥ 100,000mm3, 
 
hemoglobin >10 g/dL 
 
  
 
 
4.1.6.2 Hepatic: 
 
alkaline phosphatase ≤ 1.5 X upper limit of normal 
 
bilirubin ≤ 1.5 X upper limit of normal 
 
AST ≤ 1.5 X upper limit of normal 
 
ALT ≤ 1.5 X upper limit of normal 
 
Bilirubin for Gilbert’s ≤ 3.0 mg/dl 
 
 
 
4.1.6.3 Renal: 
 
A calculated Creatinine clearance (Cockcroft Gault) of ≥ 30 ml/min 
 
 
4.1.6.4 Electrolytes: 
 
Sodium ≥ 130 mg/dl and ≤ upper limit of normal 
 
Potassium ≥ 3.0 mg/dl and ≤ upper limit of normal 
 
 
 
*Normal limits are defined as the normal range appearing on the results report for the clinical 
laboratory providing the clinical laboratory testing. 
 
4.1.7  The effects of erlotinib on the developing human fetus at the scheduled weekly dose are 
unknown.  For this reason 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. 
 
4.1.8  Ability to understand and the willingness to sign a written informed consent 
document. 
 
4.2  
Exclusion Criteria 
 
4.2.1 
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. 
 


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4.2.2 
Any  chemotherapy and/or radiation therapy received ≤ 3 months of study entry and any 
immunotherapy received ≤ 6 months of study entry (with the execption of BCG treatment).  
 
 
4.2.2.1 Any prior external beam radiation to the pelvis. 
 
 
4.2.3 
A concurrent skin rash or skin condition requiring treatment with a prescription medication.  
 
4.2.4 
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 due to the risk of significant drug-drug interaction. 
 
• 
Coumadin 
• 
Strong CYP3A4 inhibitors (which lead to decreased erlotinib metabolism/increased erlotinib 
levels) including ketoconazole, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, 
darunavir, dasabuvir, idelalisib, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, 
ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
troleandomycin, voriconazole, and grapefruit or grapefruit juice. 
• 
 CYP3A4 inducers (which lead to increased erlotinib metabolism/decreased erlotinib levels) 
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 
 
4.2.5 
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. 
 
4.2.6 
Participants may not be receiving any other investigational agents. 
 
4.2.7 
History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to erlotinib or clindamycin (topical agent for potential skin toxicity). 
 
4.2.8 
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, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
4.2.9 
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. 
 
 


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4.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. Because of the 
demographics and incidence history at our consortium sites we expect a predominance of white males, 
which reflects the incidence of bladder cancer. The University of Wisconsin Chemoprevention 
consortium sites see an average of 76% male patients and 89% white patients. However, many of our 
consortium sites serve ethnically diverse areas. Urology San Antonio has shown successful recruitment 
with Hispanic and Latino patients (25% of diagnoses, 49.1% of the population), and Johns Hopkins 
University serves communities that are much more diverse with populations between 25-40% African-
American.  Johns Hopkins University and the Carolina Urologic Research Center of Myrtle Beach, SC 
both of which serve a more diverse patient population are recent additions to the Consortium.  The 
Carolina Urologic Research Center has one of the largest bladder cancer populations in the country. 
 
The UWCCC continues to look for innovative ways to increase the minority participation in our own 
clinical trials, despite the demographic profile of our community.  This is the focus of several initiatives 
of the UWCCC Cancer Control Program.  In addition to devising more effective means of reaching local 
minority populations, the UWCCC’s affiliate minority recruitment has been strengthened through 
affiliated research networks, examples being the Wisconsin Oncology Network or the Wisconsin Network 
for Health Research (both started by the Consortium PI/Bailey) which includes multiple clinical sites in 
Milwaukee county where underserved populations approach 20% compared to <10% in UWCCC’s 
catchment area. Another underserved population that our affiliated research networks help with is the 
rural poor and the elderly poor.  This is especially true with the Wisconsin Network for Health Research 
which has many clinic sites in rural defined areas with median incomes at or near the poverty line. In 
addition, the UWCCC has multiple ongoing initiatives to encourage underrepresented communities 
participation in health care research including efforts by Study PI/Chair, Tracy Downs, MD, who 
performs monthly outreach to local African-American churches for cancer and clinical research 
awareness. 
 
4.4 
Recruitment and Retention Plan 
 
In an attempt to address participant concerns about extra visits, missed work, and transportation expenses, 
we have minimized the number of study visits in this protocol. After the consent form is signed, all 
baseline/screening procedures and examinations will be done at one visit, including research blood  
sample collection (Urine sample collection will be collected only as pregnancy test option for women of 
child bearing potential). Participants found to be screen failures, will not be randomized and the research 
samples will be destroyed on-site.  Eligible participants will have two additional study visits, one at Day 
8* and one on the day of their surgery. 
 
*The Day 8 clinic visit is optional; a Day 8 phone contact will be required if clinic visit doesn’t occur 
 
Study brochures, posters, protocol fast fact sheets, pocket cards, and other recruitment materials will be 
developed at the CLO (Consortium Lead Organization, University of Wisconsin) and made available to 
the participating sites for use or modification. The CLO will coordinate with the other sites to develop 
comprehensive site-specific recruitment plans. 
 


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5. 
AGENT ADMINISTRATION 
 
Intervention will be administered on an outpatient basis. Reported adverse events (AEs) and potential 
risks are described in Section 6.2.  
 
5.1 
Dose Regimen and Dose Groups 
 
There will be two treatment groups for this trial: 
 
Treatment Group 1) Active study agent erlotinib 600 mg administered as four 150 mg tablets by 
mouth once weekly for 3 doses. (30 participants)  
 
Treatment Group 2) Placebo as administered as 4 placebo tablets by mouth weekly for 3 doses 
(15 participants) 
 
Randomization to each treatment group will be stratified by planned surgery (TURBT vs. cystectomy) 
and planned use of agents that significantly decrease erlotinib bioavailability.  For this study this is 
defined as tobacco use (current smoker) or daily scheduled use of proton pump inhibitors  A smoker is 
defined as an individual who has smoked ≥ 100 cigarettes in their lifetime and who currently smokes ≥ 1 
cigarette per day). 
 
5.2 
Study Agent Administration 
 
The study agent (erlotinib or placebo) will be dispensed by an investigational pharmacist or appropriate 
study staff at the participating organization (PO) and then self-administered by the participant at home.  A 
single bottle containing 16 tablets of study agent will be dispensed If the participant is unable to return to 
the institution to pick up their study agent, the agent will be mailed to them via courier.   
 
The study agent must be taken on an empty stomach (at least two hours after last eating).  After taking 
their dose of study agent the participant must wait an hour before eating anything. 
 
On Day 1, the participant will take one dose, 600 mg erlotinib or placebo in the form of four 150 mg 
erlotinib or matching placebo tablets by mouth in the evening (unless otherwise directed) on an empty 
stomach.  All 4 tablets comprising a single dose of study agent will be taken together at the same time. 
.  
On Day 8, the participant will take their second dose of study agent (600 mg erlotinib or placebo in the 
form of four 150 mg erlotinib or matching placebo tablets) on an empty stomach as instructed either in the 
clinic following the collection of blood samples for pharmacokinetics or at home.  Prior to the Day 8 
Optional Visit/Mandatory Safety Assessment Phone call, the participant will receive a reminder phone 
contact instructing the participant when to take the Day 8 dose. 
 
On Day 15 the participant will take their third dose of study agent approximately 9-18 hours before their 
scheduled surgery (600 mg erlotinib or placebo in the form of four 150 mg erlotinib or matching placebo 
tablets).  The participant will receive a reminder phone contact prior to their final study dosing day 
instructing them when to take this final dose.   
 
If surgery is delayed beyond the 16th day but less than the 23rd day, delay administration of the third dose 
until approximately 9-18 hours prior to the surgery.  If surgery is delayed to day 23 through day 28, 
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surgery is delayed beyond day 28 (four weekly study drug doses), the patient will be considered not 
evaluable for the primary endpoint.  
 
5.2.1 
Supportive Medications 
 
All study subjects will receive, along with study medication, 30 gm tube of topical Clindamycin (1%) gel 
and a 30 gm tube of topical Hydrocortisone (1%) cream. They will be instructed that at the first signs of 
painful or red acneiform skin lesions to apply twice daily (AM and PM) topical clindamycin to the 
aforementioned concerning skin lesions. If these lesions do not improve (less redness or pain) they will be 
instructed to also start applying topical hydrocortisone twice daily (AM and PM) at time points two hours 
apart from application of topical clindamycin. If red or painful skin lesions continue or worsen, study 
participants will be instructed to call study personnel to both report the toxicity and receive additional 
instructions. Examples of additional instructions include increased frequency of topical application, 
consideration of systemic antibiotics, avoiding alcohol-based skin products, etc. 
 
Subjects should be directed that if they experience diarrhea likely to be attributable to study drug they 
should use loperamide (Imodium) 2 mg (1 dose) with the first loose, watery stool, and with each watery 
stool therafter.  If the patient has 3-4 watery stools per day, they should contact their research doctor or 
coordinator. 
 
5.3 
Run-in Procedures 
 
There is no run-in phase for this study. 
 
5.4 
Contraindications 
 
While taking the study agent the participant should be instructed not to take any: 
• 
Strong CYP3A4 inhibitors including:  ketoconazole, atazanavir, boceprevir, ceritinib, 
clarithromycin, cobicistat; darunavir, dasabuvir, idelalisib, indinavir, itraconazole, lopinavir, 
nefazodone, nelfinavir, ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, 
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.  
Avoid the use of other antacids if possible.NSAIDs with the exception of ≤81 mg aspirin per day.  
Acetaminophen may be used as needed. 
• 
Participants should be instructed not to consume grapefruit or drink any beverages containing 
grapefruit juice. 
 
5.5 
Concomitant Medications 
 
Erlotinib is protein bound (92–95%) in humans and metabolized in the liver by CYP3A4 and, to a lesser 
extent, CYP1A2, and in the lungs by CYP1A1. A potential for drug-drug interaction exists when erlotinib 
is coadministered with drugs that are highly protein bound or that are potent CYP3A4 inhibitors/inducers. 
Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib 
plasma concentrations, while strong CYP3A4 inhibitors increase exposure to erlotinib. For patients who 
are being concomitantly treated with a strong CYP3A4 inhibitor, a dose reduction should be considered in 
the presence of severe AEs. For patients who are being concomitantly treated with a potent CYP3A4 
inducer, alternative treatments that lack potent CYP3A4-inducing properties should be considered.  
 


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Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its 
bioavailability. Coadministration of erlotinib with omeprazole, a proton pump inhibitor, decreased the 
erlotinib exposure and maximum concentration by 46% and 61%, respectively(Kletzl 2015); therefore, 
participants that use proton pump inhibitors concomitantly with erlotinib will be stratified to account for 
the decreased erlotinib exposure. 
 
Altered coagulation parameters and infrequent reports of bleeding events, including gastrointestinal and 
non-gastrointestinal bleeding, have been reported in patients in erlotinib clinical studies, some associated 
with concomitant warfarin administration. Patients taking warfarin or other coumadin-derivative 
anticoagulants should be closely monitored for changes in prothrombin time and International Normalized 
Ratio (INR). 
 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken 
by the participant will be documented on the concomitant medication CRF and will include start and stop 
dates, dose frequency and indication. Medications taken for a procedure (e.g., biopsy) should also be 
included.  Medications given in the hospital as part of the standard surgical protocol will not be 
documented as concomitant medications.  However, any medications given to treat an adverse or 
unexpected event following surgery will be documented. 
 
5.6 
Dose Modification 
 
Study drug will be dose reduced (by 50%) from 4 tablets to 2 tablets for any of the following events: 
 
• 
A grade 1 rash or diarrhea that the study subject finds unacceptable and desires the 50% 
dose reduction. 
• 
A grade 2 skin toxicity 
• 
A grade 2 diarrhea that does not respond to Imodium 
• 
Any toxicity or adverse event > grade 3 
• 
MD discretion for side effects assessed as at least possibly related to the study drug and 
for which the study subject finds unacceptable and desires the 50% dose reduction 
 
Subjects that meet the above dose modification criteria even after a dose reduction will not receive any 
further doses. At the first report of grade 1 or 2 skin toxicity, subjects should be instructed on using the 
dispensed topical ointments (1% Clindamycin, 1% hydrocortisone): apply twice daily (not at the same 
time) each ointment to the affected area only.  Subjects who report grade 1 or 2 diarrhea likely to be 
attributable to study drug should be instructed to use loperamide (Imodium) 2 mg after each loose stool. 
Provide participants with a copy of Appendix B. 
 
5.7 
Adherence/Compliance 
 
5.7.1 
Compliance (tablet ingested/tablet instructed to take) will be assessed, but only subjects who take 
all study drug weekly for 3 doses (or 4 doses due to surgery delay) will be evaluable for the primary 
endpoint. 
 
5.7.2 
Compliance will be assessed via subject questioning, returned tablet 
 count and planned drug levels. 
 
6. 
PHARMACEUTICAL INFORMATION 
 


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6.1 
Study Agent (IND # 64,808: IND Sponsor:  NCI, DCP) 
 
Clinical studies investigating the chemopreventive efficacy of erlotinib are conducted under IND 64808 
sponsored by NCI, DCP. Erlotinib (Tarceva®) is an epidermal growth factor receptor (EGFR) inhibitor 
approved by the FDA as monotherapy for the treatment of patients with locally advanced or metastatic 
non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. It is also 
indicated as first-line therapy for treatment of patients with locally advanced, unresectable, or metastatic 
pancreatic cancer in combination with gemcitabine. 
 
Erlotinib drug product will be supplied as the hydrochloride (HC1) salt by Astellas Pharma Global 
Development, Inc. Erlotinib is currently formulated as conventional, immediate-release tablets in 25 mg, 
100 mg, and 150 mg strengths. For the purpose of this study, the 150 mg strength tablet will be used.  
Erlotinib drug substance is an off-white to pale yellow powder. Conventional excipients in the 
formulation include lactose monohydrate, hypromellose, hydroxypropyl cellulose, microcrystalline 
cellulose, sodium starch glycolate, sodium lauryl sulfate, magnesium stearate, and titanium dioxide.  
 
Matching placebo tablets will be manufactured containing lactose monohydrate, microcrystalline 
cellulose, croscarmellose sodium and magnesium stearate. 
 
6.2 
Reported Adverse Events and Potential Risks 
 
Over 50 Astellas (formerly OSI Pharmaceuticals, Inc.)-sponsored phase 1, 2, and 3 clinical studies of 
erlotinib have been initiated or completed. Various doses and schedules of erlotinib as a single agent and 
in combination with conventional chemotherapy agents have been studied. Twelve phase 1 studies have 
been conducted in healthy volunteers to determine the safety, tolerance, pharmacology, and 
pharmacokinetics of erlotinib (n = 268). The phase 1 healthy subject experience is based on the use of 
different oral erlotinib doses and schedules ranging from single-dose administration of 1–1000 mg to 
administration of 200 mg twice daily (bid) compared with placebo. Early tolerability studies showed that 
200 mg erlotinib bid was associated with dose-limiting rash and diarrhea in addition to reversible liver 
transaminase elevation. Subsequent single- or multiple-dose pharmacology studies of 100 or 150 mg 
erlotinib daily did not reveal any new safety findings; however, the characteristic acneiform rash was 
unacceptable in healthy subjects receiving 150 mg erlotinib daily for approximately 1 week or longer. The 
phase 1 experience in cancer patients includes studies with different erlotinib doses and schedules. The 
maximum tolerable dose (MTD) of single-agent erlotinib was determined to be 150 mg daily, with 
diarrhea being the dose-limiting toxicity (DLT) despite supportive antidiarrheal treatment. Weekly dosing 
of erlotinib up to 1600 mg did not define an MTD; however, severe drug-related skin disorders were 
reported for patients receiving 1400 and 1600 mg weekly.  
 
The phase 1b studies were designed to evaluate the MTD and pharmacokinetics of erlotinib when 
combined with standard doses of common chemotherapy regimens. The patient populations in these trials 
in general consist of advanced, refractory cancer patients with limited therapeutic options. As expected, 
patients who received concomitant chemotherapy in each of these trials experienced more hematological 
toxicities including anemia, neutropenia, and thrombocytopenia than patients who received erlotinib as a 
single agent therapy.  
 
In a phase 2 trial of neoadjuvant erlotinib at 150 mg daily in invasive bladder cancer patients undergoing 
radical cystectomy, rash was the most common AE, observed in 15 patients (75%). 
 
Other adverse events (AEs), including fatalities, have been reported in patients receiving erlotinib for 
treatment of NSCLC, pancreatic cancer, or other advanced solid tumors, based on the safety evaluations 


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of erlotinib in more than 1200 cancer patients who received erlotinib as monotherapy, more than 300 
patients who received 100 or 150 mg erlotinib plus gemcitabine, and 1228 patients who received erlotinib 
concurrently with other chemotherapies. 
 
The most common AEs in patients receiving single-agent erlotinib at 150 mg for treatment of NSCLC in 
the 2nd/3rd line study were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, 
respectively, of erlotinib-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% 
of erlotinib-treated patients. Dose reduction for rash and diarrhea was needed in 6% and 1% of patients, 
respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 
12 days. Liver function test abnormalities (including elevated ALT, AST, and bilirubin) were also 
observed. These elevations were mainly transient or associated with liver metastases. Grade 2 (>2.5–5.0 × 
ULN) ALT elevations occurred in 4% and <1% of erlotinib- and placebo-treated patients, respectively. 
Grade 3 (>5.0–20.0 × ULN) elevations were not observed in erlotinib-treated patients.  
 
In the NSCLC maintenance study, the most common adverse reactions in patients receiving single-agent 
erlotinib at 150 mg were also rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 6% and 1.8%, 
respectively, of erlotinib-treated patients. Rash and diarrhea resulted in study discontinuation in 1.2% and 
0.5% of erlotinib-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was 
needed in 5.1% and 2.8% of patients, respectively. In erlotinib-treated patients who developed rash, the 
onset was within two weeks in 66% and within one month in 81%. Liver function test abnormalities 
(including elevated ALT, AST, and bilirubin) were also observed. Grade 2 (>2.5–5.0 × ULN) ALT 
elevations occurred in 2% and 1%, and grade 3 (>5.0–20.0 × ULN) ALT elevations were observed in 1% 
and 0% of erlotinib- and placebo-treated patients, respectively. The erlotinib treatment group had grade 2 
(>1.5–3.0 × ULN) bilirubin elevations in 4% and grade 3 (>3.0–10.0 × ULN) in <1% compared with <1% 
for both grades 2 and 3 in the placebo group.  
 
The most common AEs in pancreatic cancer patients receiving 100 mg erlotinib plus gemcitabine were 
fatigue, rash, nausea, anorexia, and diarrhea. In the erlotinib/gemcitabine arm, grade 3/4 rash and diarrhea 
were each reported in 5% of patients. The median time to onset of rash and diarrhea was 10 days and 15 
days, respectively. Rash and diarrhea each resulted in dose reductions in 2% of patients and resulted in 
study discontinuation in up to 1% of patients receiving erlotinib/gemcitabine. The 150 mg cohort was 
associated with a higher rate of certain class-specific AEs including rash and required more frequent dose 
reduction or interruption.  
 
In the pancreatic carcinoma trial, 10 patients in the erlotinib/gemcitabine group developed deep venous 
thrombosis (incidence 3.9%), compared with three patients in the placebo/gemcitabine group (incidence 
1.2%). The overall incidence of grade 3 or 4 thrombotic events, including deep venous thrombosis, was 
similar in the two treatment arms: 11% for erlotinib/gemcitabine vs. 9% for placebo/gemcitabine. No 
differences in grade 3 or 4 hematologic laboratory toxicities were detected between the 
erlotinib/gemcitabine group compared with the placebo/gemcitabine group. AEs ≥ grade 3 in the 
erlotinib/gemcitabine group with incidences <5% included syncope, arrhythmias, ileus, pancreatitis, 
hemolytic anemia including microangiopathic hemolytic anemia with thrombocytopenia, myocardial 
infarction/ischemia, cerebrovascular accidents including cerebral hemorrhage, and renal insufficiency. 
Liver function test abnormalities (including elevated ALT, AST, and bilirubin) were also observed. The 
erlotinib/gemcitabine treatment group had grade 2 (>2.5–5.0 × ULN) ALT elevations in 31% and grade 3 
(>5.0–20.0 × ULN) elevations in 13% compared with 22% for grade 2 and 9% for grade 3 in the 
placebo/gemcitabine group.  
 
There have been infrequent reports of serious Interstitial Lung Disease (ILD)-like events, including 
fatalities, in patients receiving erlotinib for treatment of NSCLC, pancreatic cancer or other advanced 
solid tumors. In the randomized single-agent NSCLC study the incidence of ILD-like events was the same 


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in both the placebo and erlotinib groups (0.8%). In the pancreatic cancer study (in combination with 
gemcitabine) the incidence of ILD-like events was 2.5% in the erlotinib/gemcitabine group vs. 0.4% in 
the placebo/gemcitabine group. The overall incidence of ILD-like events in approximately 32,000 
erlotinib-treated patients from all studies (including uncontrolled studies and studies with concurrent 
chemotherapy) was approximately 1.1%. Reported diagnoses in patients suspected of having ILD-like 
events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, 
interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress 
Syndrome, and lung infiltration. Symptoms started from five days to more than nine months (median 39 
days) after initiating erlotinib therapy. In the lung cancer trials most of the cases were associated with 
confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre-
existing parenchymal lung disease, metatstatic lung disease, or pulmonary infections. 
 
During the NSCLC and the combination pancreatic cancer trials, infrequent cases of gastrointestinal 
bleeding have been reported, some associated with concomitant warfarin or NSAID administration. These 
adverse events were reported as peptic ulcer bleeding (gastritis, gastroduodenal ulcers), hematemesis, 
hematochezia, melena, and hemorrhage from possible colitis. Cases of acute renal failure or renal 
insufficiency, including fatalities, with or without hypokalemia have been reported. Cases of grade 1 
epistaxis were also reported in both the single-agent NSCLC and the pancreatic cancer clinical trials. 
Corneal ulcerations or perforations have been reported in patients receiving erlotinib. Abnormal eyelash 
growth, including in-growing eyelashes, excessive growth, and thickening of the eyelashes have been 
reported and are risk factors for corneal ulceration/perforation. Grade 3 conjunctivitis and keratitis have 
been reported infrequently in patients receiving erlotinib therapy in the NSCLC and pancreatic cancer 
clinical trials. Hepatic failure has been reported in patients treated with single-agent erlotinib or erlotinib 
combined with chemotherapy in clinical studies and during post marketing use of erlotinib.  
 
Bullous, blistering, and exfoliative skin conditions have been reported, including cases suggestive of 
Stevens-Johnson syndrome/Toxic epidermal necrolysis. In patients who develop skin rash, the appearance 
of the rash is typically erythematous and maculopapular and it may resemble acne with follicular pustules, 
but is histopathologically different. This skin reaction commonly occurs on the face, upper chest, and 
back, but may be more generalized or severe (grade 3/4) with desquamation. Skin reactions may occur or 
worsen in sun-exposed areas; therefore, the use of sunscreen or avoidance of sun exposure is 
recommended. Associated symptoms may include itching, tenderness, and/or burning. Also, 
hyperpigmentation or dry skin with or without digital skin fissures may occur. Hair and nail disorders, 
including alopecia, hirsutism, eyelash/eyebrow changes (mentioned above), paronychia, and brittle and 
loose nails have also been reported. 
 
In the pancreatic carcinoma trial, six patients (incidence 2.3%) in the erlotinib/gemcitabine group 
developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In 
comparison, three patients in the placebo/gemcitabine group developed myocardial infarction (incidence 
1.2%) and one died due to myocardial infarction. In the same trial, six patients in the 
erlotinib/gemcitabine group developed cerebrovascular accidents (incidence 2.3%). One of these was 
hemorrhagic and was the only fatal event. In contrast, there were no cerebrovascular accidents in the 
placebo/gemcitabine group. In the same trial, two patients in the erlotinib/gemcitabine group developed 
microangiopathic hemolytic anemia with thrombocytopenia (incidence 0.8%), compared with no patients 
in the placebo/gemcitabine group. 
 
Cases of hepatorenal syndrome, acute renal failure (including fatalities) or renal insufficiency with or 
without hypokalemia have been reported. Some were secondary to severe dehydration due to diarrhea, 
vomiting, and/or anorexia while others were confounded by concurrent chemotherapy use. Asymptomatic 
increases in liver transaminases have been observed in erlotinib-treated patients. Rare cases of hepatic 
failure (including fatalities) have been reported during post marketing use of erlotinib. Confounding 


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factors for severe hepatic dysfunction have included pre-existing liver dysfunction from cirrhosis, viral 
hepatitis, hepatocellular carcinoma, hepatic metastases, or concomitant treatment with potentially 
hepatotoxic drugs.  
 
Erlotinib can cause fetal harm when administered to a pregnant woman; therefore, women should avoid 
becoming pregnant while being treated with erlotinib. Adequate contraceptive methods should be used 
during therapy and for at least two weeks after completing therapy. There are no adequate and well-
controlled studies in pregnant women using erlotinib; however, studies in animals have shown some 
reproductive toxicity. Breastfeeding should be discontinued during erlotinib therapy. While it is not 
known whether erlotinib is excreted in human milk, in animals erlotinib and/or its metabolites were 
excreted in milk.  
 
Please see Concomitant Medications Section.  
 
6.3  
Availability 
 
Erlotinib and matching placebo are manufactured and supplied to NCI/DCP by Astellas Pharma Global 
Development, Inc. (Northbrook, IL). 
 
6.4 
Agent Distribution 
 
Drug Shipment Authorization allowing study agent to be shipped to a participating organization will only 
be provided by NCI, DCP after documentation of IRB approval of the DCP-approved protocol and 
consent is provided to DCP and the collection of all Essential Documents is complete (see DCP website 
for description of Essential Documents).  
 
Requests for shipment of study agent will be made by the CLO. DCP guidelines require that the agent be 
shipped directly to the institution or site where the agent will be prepared and administered. DCP does not 
permit the transfer of agents between institutions (unless prior approval from DCP is obtained). DCP does 
not automatically ship agents; the CLO must make a request. Agents are requested by completing the 
DCP Clinical Drug Request form (NIH-986) (to include complete shipping contact information) and 
faxing or mailing the form to the DCP agent repository contractor: 
 
John Cookinham 
MRIGlobal 
DCP Repository 
425 Volker Blvd. 
Kansas City, MO 64110   
Phone:  (816) 360-5369 
FAX:  (816) 753-5359 
Email: NCI.DCP@mriglobal.org 
Emergency Telephone: (816) 360-3800 
 
6.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of 
the inventory and disposition of all agents received DCP using the NCI “Investigational Agent 
Accountability Record”. The Investigator is required to maintain adequate records of receipt, dispensing 
and final disposition of study agent. This responsibility has been delegated to investigational pharmacist 
or study coordinator at each site.  Include on receipt record from whom the agent was received and to 


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whom study agent was shipped, date, quantity and batch or lot number.  On dispensing record, note 
quantities and dates study agent was dispensed to and returned by each participant.  
 
 
 
6.6 
Packaging and Labeling 
 
Erlotinib and matching placebo will be packaged and labeled by the DCP agent repository contractor, 
MRIGlobal. For the treatment period, participants will be supplied with bottles containing identically 
appearing tablets containing either 150 mg erlotinib or placebo, according to the dose cohort. 
Investigational products will be supplied in bottles containing 16* tablets each of study agent (*pending 
repackaging, we will continue to dispense bottles containing 24 tablets with specific instructions to only 
take  600 mg as four 150 mg tablets per dose).  Each bottle will be labeled with the following content: 
protocol number, storage information, investigational use language (Caution: New Drug Limited by 
Federal Law to Investigational Use Only. Keep out of reach of children”), and instructions to take as 
directed. Prior to dispensing investigational product, trial personnel will attach a label containing the 
participant identification number, randomization number, and dispensing date.  
 
6.7 
Storage 
 
Erlotinib and placebo tablets are supplied in high density, polyethylene bottles and should be stored in a 
secure location.  Storage will be maintained at 25° C (77°F); excursions permitted to 15°C - 30°C (59°F - 
86°F).  See USP Controlled Room Temperature. 
 
 
6.8 
Registration/Randomization 
 
Participants will be considered registered on the trial when they sign the consent form. All patients who 
sign a consent form will be assigned a Participant Identification (PID) number. A set of unique sequential 
PID numbers will be provided to the PO in the form of a Study Registration Log. This log will be 
provided to the PO by the CLO at the study initiation. 
 
Randomization 
Participants will be randomized according to the scheme outlined in section 3. The study statisticians will 
provide the CLO with a stratified list of randomization numbers.  The DCP Drug repository will also be 
provided with the list along with the treatment assignment that corresponds to each randomization 
number.  
 
When an eligible participant is identified at the screening/baseline visit, the site will request 
randomization of the participant by faxing the appropriate documentation as outlined in the Study Visit 
Guides to the CLO at 608-265-3287. 
 
 
 
 
The CLO will verify eligibility and confirm that the correct version of the informed consent was signed.  
Once this information is verified, the CLO will assign the next available randomization number from the 
stratification that applies to the participant (TURBT vs. cystectomy and use of agents which significantly 
decrease erlotinib bioavailability ).  The CLO will then fax an Investigational Agent Request form to the 
DCP drug repository requesting that the bottle of study agent corresponding to the randomization number 


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assigned the participant be shipped to the site’s (investigational) pharmacy by overnight delivery.  The 
site will follow local procedures to have the study agent dispensed to the participant once it is received at 
the pharmacy. 
 
For next day delivery of study agent, the request for randomization must be received at the CLO office by 
2:30 PM Eastern Time (1:30 PM Central Time) on the business day before the drug is needed.  Per NCI 
policy, drug cannot be shipped on a Friday or the day before a holiday. There may be instances where a 
five-day turn-around is needed (holidays or unusual circumstances). If possible, please randomize a week 
before the drug is needed.  
 
As soon as a subject has been randomized, the CLO will email a confirmation of randomization to the 
study coordinator at the PO. If a confirmation is not received within two hours, the coordinator should 
contact the CLO to confirm that randomization documents were received. 
 
6.9 
Blinding and Unblinding Methods 
 
Unblinded study personnel will be the study statisticians, and the DCP Drug repository staff. No staff 
involved in patient care or assay performance and interpretation will be unblinded. All participants will be 
administered identical drug, so the study staff will be blinded to both the treatment and dose level. All 
drug will be dispensed and reordered according to kit number, and so the pharmacy staff will all remain 
blinded to treatment. 
 
All requests to unblind treatment assignment will be funneled to the Consortium Principal Investigator 
[Howard H. Bailey, (608) 263-8624, hhb@medicine.wisc.edu]. Dr. Bailey will determine if disclosure of 
treatment assignment is required after consultation with the NCI/DCP medical monitor (Howard Parnes, 
MD) and/or the protocol chair (Dr. Downs) or the Data and Safety Monitoring Board. Except in cases of 
emergency, decisions regarding unblinding of the treatment group of a randomized subject will be made 
in consultation with the NCI/DCP medical monitor, Dr. Howard Parnes. If disclosure of the treatment 
would affect important medical decisions in a subject experiencing an adverse event, unblinding might be 
allowed. Other circumstances might warrant breaking the blind but the decision will be left to the Dr. 
Bailey and the DSMB. Authorization for unblinding of randomized treatment will come from Dr. Bailey 
or the DCP Medical Monitor. If disclosure is warranted, the site will be directed to the product label 
found in the subject’s CRF binder or other designated research record. The label has a scratch off area 
that will disclose the treatment. The site will complete an Unblinding Disclosure Form and send it to the 
CLO [K4/643, 600 Highland Avenue, Madison, WI 53792-6164 or Fax (608) 265-3287]. Each site will 
document the unblinding process in the patient chart. 
 
The NCI Medical Monitor and/or Scientific Monitor will be notified that the blind has been broken. 
 
Howard Parnes, MD 
Prostate and Urologic Cancer Research Group 
Division of Cancer Prevention, National Cancer Institute, NIH, DHHS 
 
Shady Grove Campus 
 
9609 Medical Center Dr., Suite 5E-302 
 
Rockville, MD 20850 
 
Phone: (240) 276-7045;  
 
parnesh@mail.nih.gov 
 
6.10 
Agent Destruction/Disposal 
 


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All returned drug will be maintained at the site until a representative from the CLO has verified all 
pharmacy records. Once the CLO representative has reviewed the drug records, he or she will authorize 
the return of the drug to the DCP Repository. The site may then return the drug to the DCP repository for 
destruction. 
 
At the completion of the study, all unused study agent will be returned to NCI, DCP Repository according 
to the DCP “Guidelines for AGENT RETURNS” and using the DCP form “Return Drug List”.  
 


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7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Events 
 
Evaluation/ 
Procedure 
Pre-Study 
Evaluation/ 
Baseline 
(≤30 days) 
Randomize
/ Dispense 
Study 
Agent 
 
Phone 
Contact 
(24-72 
hours 
Prior to 
Day 8 
Visit)  
Day 8 
Visit7 
Pre-surgery 
phone 
contact (24-
72 hours 
prior to 
surgery) 
Surgery Visit 
(day 15-16) 
Post-surgery 
Phone 
Contact (7-
14 days 
after 
surgery) 
Informed Consent 
X 
 
 
 
 
 
 
Assess Eligibility 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X2 
 
 
X2 
 
X2 
 
Baseline Symptoms 
X 
 
 
 
 
 
 
Vital signs (temp, pulse, 
BP, Ht and Wt) 
X 
 
 
X 
 
X 
 
Hgb, Hct, WBC, Plt 
X 
 
 
X 
 
X 
 
Na, K, CO2, Cl 
X 
 
 
X 
 
X 
 
BUN,Creat 
X 
 
 
X 
 
X 
 
AST, ALT, Alk Phos 
X 
 
 
X 
 
X 
 
T Bili 
X 
 
 
X 
 
X 
 
Urine or Serum 
Pregnancy Test 
X 
 
 
 
 
 
 
Blood for PK 
X 
 
 
X 
 
X 
 
Tissue Blocks/slides 
 
 
 
 
 
X 
 
Concomitant Meds 
X 
 
 
X7 
 
X 
X 
Dose of study agent 
 
X1  
 
X3 
X4,5 
 
 
Dose reminder call 
 
 
X 
 
X 
 
 
Dispense 1% 
clindamyacin & 1% 
hydrocortisone 
 
X6 
 
 
 
 
 
I-PSS (men only) 
X 
 
 
 
 
X 
 
Compliance 
 
 
 
X7 
 
X 
 
Adverse Events 
 
 
 
X7 
 
X 
X 
 
1. 
The date of the Day 1 dose equals the date of the surgery minus 15 days.  For example, if the surgery was on the 23rd of the month, 23-
15= 8, therefore the participant would take their 1st dose of study agent on the 8th of the month. 
2. 
Physical exam should include evaluation for rash.  If a rash is noted, document the extent of the rash per CTCAE grading criteria 
3. 
The Day 8 dose of study agent should be taken during the clinic visit after the pharmacokinetic blood draw is completed or at home as 
instructed by study staff. 
4. 
The pre-surgical dose of study agent should be taken in the evening prior to the day of surgery and within approximately 9-18 hours of 
the time of the pre-surgery pharmacokinetic blood draw. 
5. 
If surgery is delayed beyond the 16th day but less than the 23rd day, delay administration of the third dose until the evening prior to 
the day of surgery.  If surgery is delayed to day 23 through day 28, administer the third dose at day 15 and the fourth dose in the 
evening prior to  day of scheduled surgery. If surgery is delayed beyond day 28 (four weekly study drug doses), the patient will be 
considered not evaluable for the primary endpoint.  A reminder phone contact should be made 72 – 24 hours prior to the day of the re-
scheduled surgery. 


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6. 
Dispense to all study participants when dispensing medication per NCI requirements.  Instruct participant to use these agents for skin 
toxicities. 
7. 
 Day 8 clinic visit will be optional; if participant opts out a mandatory phone call to review safety assessments will be required within 
48 hours of taking the Day 8 dose. 
 
 
All participants who sign a consent form will be assigned a registration number. The consent form must 
be signed before any research procedures may be performed. The assigned registration number will be 
tracked using the registration log provided by the CLO. Registered participants need to be entered into the 
OnCore database.  
 
7.2 
Baseline Testing/Prestudy Evaluation 
 
Baseline Evaluations 
Baseline evaluations determine if the participant is a fit candidate for study participation and establish the 
participant's health status before entering the study. Standard-of-care labs or procedures done prior to 
signing consent will qualify for these baseline evaluations (i.e. physical exams, routine labs, vital signs) 
provided they were obtained within 30 days of the participant’s Day 1 dose of study agent. All baseline 
evaluations (including labs) must be completed before requesting randomization and dispensing study 
drug. An Eligibility Checklist will be provided by the CLO at study initiation to help determine if the 
participant is eligible for the trial. This document will need to be signed and submitted to the CLO at the 
time of randomization. 
 
Baseline cystoscopy demonstrating a bladder tumor. The physician should assess if the bladder tumor is 
invasive or non-invasive. The baseline cystoscopy must be completed within 120 days of randomization. 
 
At the screening/baseline visit, blood for pharmacokinetics may be collected before eligibility has been 
confirmed.  However, if the participant is later found to be ineligible, the sample may not be used. If the 
participant is found to be ineligible, clearly document the destruction of the pharmacokinetic blood 
sample in the participant’s research chart.  
 
A review of the participant's medical history will be done within 30 days of randomization. 
 
A physical examination must be performed within 30 days of randomization. 
 
Performance Status, using the Karnofsky must be assessed 
 
A review of concomitant medications will be done within 30 days of randomization. 
 
Laboratory tests needed for eligibility are: WBC, platelets, hemoglobin, total bilirubin, AST, ALT, 
alkaline phosphatase, creatinine, sodium and potassium. All of these laboratory analyses must be 
completed within 30 days before randomization. 
 
Women of child-bearing potential must have a negative pregnancy test within 30 days of randomization. 
 
Plasma Pharmacokinetics - Levels of erlotinib and metabolites will be assessed for all participants.   
 
International Prostate Sympyom Score (I-PSS) – The participant will complete the survey within 30 
days of randomization 
 
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study visits and procedures with the participant. The participant should be provided a study calendar to 
record any side effects and the time the participant takes their study medication. The participant should be 
strongly encouraged to contact the research staff with questions about study participation. 
 
Randomization and Drug Request 
Once the eligibility evaluations have been completed and the participant meets all of the inclusion criteria 
in section 4.1 and meets none of the exclusion criteria in section 4.2, then the participant may be 
randomized to the trial. Before the participant may be randomized, the Eligibility Checklist must be 
completed and signed.  Refer to section 6.8 for specific instructions on participant randomization. 
 
7.3 
Evaluation During Study Intervention 
 
Special Drug Dosing Procedures 
The participant must be instructed to take the medication in the evening on an empty stomach (no food 
within two hours before ingestion and within one hour post-ingestion) on day 1, 8 and 15 with the 
scheduled surgery on day 16. To ensure compliance, participants will be instructed verbally and in writing 
to take 4 tablets from their dispensed bottle on the scheduled evenings (study days 1, 8, and 15). 
 
Drug Dispensing 
Study agent will be shipped to the PO on a per participant basis.  The request to ship study agent will be 
sent by the CLO once a request for participant randomization has been received from the site and 
eligibility has been verified by the CLO (refer to section 6.8).  The bottle of study agent shipped to the PO 
will be identified with the randomization number assigned to the participant.  When the participant’s 
study agent arrives at the PO it may be dispensed to the participant. If the institution requires a 
prescription for investigational agents, the site coordinator or pharmacy staff must clearly document that 
all prescription procedures were followed before drug was dispensed to the participant. 
 
Reminder Phone Contact Before Day 8 Visit 
Approximately twenty four to seventy two hours before the Day 8 Visit, the participant will be contacted 
by phone and reminded about their Day 8 appointment time.  The participant will also be reminded about 
study dose (timing, any dose modifications, how to take it, etc.). 
 
Day 8 Visit* 
Participants will be seen and evaluated by research staff on day 8 prior to ingesting their day 8 study dose. 
The evaluation includes vital signs, review any adverse events that took place including an assessment of 
toxicities (especially skin toxicity and diarrhea) and concomitant medications.  Blood for safety labs and 
pharmacokinetics will be obtained. The coordinator should collect and calculate study drug compliance.  
If dose modifying toxicity (as described above) has occurred, study staff will instruct the participant on 
their modified study dose (3 tablets) for day 8 and 15. After completion of this assessment the day 8 study 
dose will be taken as instructed.  
 
*Day 8 clinic visit is optional.  If participant decides to opt out; a Day 8 phone call to evaluate safety 
assessments will be required.  This phone call should occur after the day 8 dose is taken and within 48 
hours of the dosing.  The call should include an evaluation of toxicities, a review of concomitant 
medications and compliance. 
 
Reminder Phone Contact Before Surgery 
Approximately twenty four to seventy two hours before surgery or cystoscopy with biopsy, the participant 
will be contacted by phone and reminded about their last study dose (timing, any dose modifications, how 
to take it, etc.) and returning any leftover study medication and study medication bottles to the research 


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staff.  The participant will also be reminded about the appointment(s) on the day of surgery with study 
staff.   
 
7.4 
Evaluation at Completion of Study Intervention 
 
At the end of study participation, the participant will have research blood work and evaluations for 
toxicity.  The results of these analyses will be compared to the baseline results.  At the end of study 
intervention the following procedures must be completed.  The end of study visit has some critical timing 
requirements to allow for accurate pharmacokinetic measurements in the blood. The final dose of study 
drug should be taken on the day before surgery on an empty stomach. The participant should be instructed 
to take this final dose in the evening prior to the day of their surgery. The end-of-study pharmacokinetic 
blood work must happen approximately 9-18 hours after the last dose of study drug was taken.  Please 
document the date and hour: minute of the last study dose along with the date and hour: minute of the 
pharmacokinetic blood draw. 
 
Laboratory analyses for safety:  WBC, platelets, hemoglobin, Hct, BUN, total bilirubin, AST, ALT, 
alkaline phosphatase, creatinine, sodium, potassium, chloride and bicarbonate. 
 
The participant’s vital signs, including weight, blood pressure, pulse rate, respiration rate and 
temperature will be taken. 
 
A review of concomitant medications focusing on any changes to the medication list since study 
initiation and any new medications started since study initiation. Participants should be questioned about 
medications that have been discontinued prior to surgery. 
 
The coordinator should collect and calculate study drug compliance. 
 
International Prostate Sympyom Score (I-PSS) – would be completed prior to surgery and the 
coordinator would collect this. 
 
The participant and coordinator should review any adverse events that took place during study 
participation. The coordinator should record the relevant details about the adverse events as 
outlined in protocol section 11. 
 
To insure consistency in pharmacokinetic evaluations, all participants should have their end-of-study 
pharmacokinetic blood work and biomarkers within approximately 9-18 hours after the final dose of study 
medication. See section 10.2.2 for instructions on drawing and processing the end-of-study 
pharmacokinetics and biomarkers. Record the date and time of the pharmacokinetic blood draw and the 
date and time of the last dose of study drug. 
 
Interventions at Time of Surgery 
At the time of the study surgery (TURBT or cystectomy) biopsies from tumor (if available and may be 
invasive or non-invasive neoplasm) and adjacent normal appearing urothelium should be performed. 
Unstained slides or blocks relative to tumor and adjacent normal urothelium will be obtained. Detailed 
instructions for collection are found in section 10.2. 
 
7.5 
Post-intervention Follow-up Period 
 
Surgery and pathology reports from the surgical procedure should be added to the participant chart. 
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immunohistochemical analysis. See section 10.2.4 for more details. If the tissue blocks are required for 
future diagnostics or care, the request for tissue blocks may be delayed up to 2 months after surgery to 
provide adequate time for evaluation. 
 
Phone Contact after Surgery 
Approximately 7-14 days after surgery, subjects will be called by research staff to assess any toxicity 
related to the day 15 study drug dose and when it has resolved. 
 
7.6 
Methods for Clinical Procedures 
 
There are no special clinical procedures that require additional instructions in this protocol. 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
 
The primary goal is assessing whether there is sufficient tissue delivery and duration of effect to justify 
the continued testing of weekly administered erlotinib. Because erlotinib is a targeted tyrosine kinase 
inhibitor of EGFR phosphorylation measuring that is the best way to assess tissue effects.  Multiple 
studies have shown inhibition (from moderate to complete) of EGFR phosphorylation in skin and less 
consistent inhibition in tumor (Perez-Soler 2011, Calvo 2007).  Of note, this measured inhibition has not 
always correlated with positive or negative biological effects (effectiveness/toxicity). Because we aren’t 
trying to determine effectiveness, but rather any biological effect in bladder epithelium without clinically 
limiting toxicity for prevention, EGFR phosphorylation in bladder epithelium is the ideal marker. Our 
primary tissue of interest is the normal appearing urothelium adjacent to bladder neoplasia since we are 
very interested in preventing the field cancerization effect seen in progressive, high grade superficial 
bladder cancer. We intend to examine EGFR phosphorylation in tumor as well.  We are assessing 
biological effects of intermittent, high dose erlotinib therefore our premise is that intermittent inhibition 
of EGFR phosphorylation should be of sufficient duration (≥ 24 hours) to have a reasonable likelihood of 
perturbing bladder carcinogenesis. For this initial pilot study assessing intermittent erlotinib in a bladder 
prevention study we will assess bladder urothelium approximately 9-18 hours post-dosing of study 
drug. Methodology Summary - three primary antibodies will be simultaneously stained and detected 
on patient tissue samples [cytokeratin AE1/AE3 (black), anti-EGFR(brown) and anti-EGFR phosphor 
(red].  Multispectral immunohistochemstry will be used to detect these two targets simultaneously 
(phosphorylated EGFR and EGFR). Hematoxylin will be used as counterstain. Since phosphorylated 
EGFR and EGFR are located on cell membrane including cytoplasmic membrane, endoplasmic 
reticulum membrane, Golgi apparatus membrane, nucleus membrane and endosome membrane. We will 
acquire quantitative measurement (mean optical density per pixel area) from tumor epithelium and 
adjacent normal urothelium. Please see Section 9 for additional detail. 
 
8.2 
Secondary Endpoints 
 
Tolerance. The recommended dosing in adults of erlotinib is a daily oral dose of 150 mg continuously or 
until dose-limiting toxicity leads to an interruption and possible reduction in daily dosing. Since the 
advent of phase 1 and 2 studies of erlotinib and gefitinib, the dose-limiting toxicity has been painful rash 
or less commonly diarrhea. Grade 1 or 2 rash which is relatively common even at the lowest daily doses, 
approximately 50 mg, and is reluctantly tolerated even by patients with advanced cancer (Perez-Soler 
2011).  The cutaneous toxicity is an inflammatory follicular rash in the face and, less frequently, in the 
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been fully elucidated, but the leading hypothesis is that the keratinocytes of the basal layer of the 
epidermis reacts to EGFR inhibition by secreting cytokines that trigger an inflammatory response that 
eventually causes loss of skin barrier protection and secondary skin infections involving mainly the hair 
follicles (Perez-Soler 2011).  Attempts to ameliorate this skin toxicity have been of questionable 
effectiveness and there is no standard procedure other than symptomatic treatments and dose 
discontinuation (Perez-Soler 2011). Clinicians and researchers have attempted to ameliorate the frequency 
and severity of cutaneous toxicity through intermittent dosing, which is the premise behind this study. 
Milton et al. (Milton 2006) performed a dose-escalation study in 14 advanced NSCLC patients who 
received doses of 1200, 1600 and 2000 mg once weekly. Rash and diarrhea were the most frequent 
toxicities. Eleven of 12 evaluable Phase I patients experienced Grade 1 or 2 rash. The rash generally 
persisted but improved with continued weekly dosing. Of the 5 patients who developed Grade 2 rash in 
the Phase I portion of the trial, most did so within 2 weeks of starting erlotinib. The rash lasted 1 or 2 
weeks in 3 patients and >4 weeks in 2 patients. These 5 patients were given topical clindamycin and/or 
oral minocycline. Similarly, 11 of 12 patients experienced Grade 1 or 2 diarrhea. Diarrhea generally was 
experienced within 24 to 48 hours of drug administration and was controlled well with loperamide 
therapy given on an as-needed basis.  Thirteen additional patients were enrolled at 2000 mg weekly, again 
the vast majority experienced grade 1-2 rash and diarrhea.  Grade 2 rash with weekly erlotinib was more 
frequent numerically with dose escalation and developed in 42% of patients who received 2000 mg and in 
17% of patients who received 1200 mg or 1600 mg. Pertinent to this study, of the 6 patients treated at 
1200 and 1600 mg dose levels, all six developed at least grade 1 rash or diarrhea. Therefore, assessing the 
tolerance of weekly erlotinib in a bladder cancer patient population will help determine the clinical 
viability of intermittent weekly erlotinib as a potential bladder cancer preventive agent either alone or in 
combination. 
 
Urothelial tissue markers.  EGFR phosphorylation will also be assessed in neoplastic urothelium where 
our prior studies, like others, have shown increased expression of phosphorylated EGFR. Our ability to 
assess all the proposed tissue markers from blocks means we will have the opportunity in some 
participants (those undergoing cystectomy for invasive disease should have blocks available from their 
initial diagnostic cystoscopy; and participants with high grade non-invasive bladder neoplasm undergoing 
a 6 week post-TURBT surveillance cystoscopy and biopsies will also have their initial TURBT tissue 
blocks) to assess the proposed tissue biomarkers before and after study drug exposure.  
 
There are numerous “downstream” biomarkers associated with EGFR phosphorylation/activation with 
examples being PI3Kinase, STAT3 or MAPKinase pathways (Bellmunt 2003, Black 2007, MacLaine 
2008). We are choosing to focus on pathways that have recently been observed to correlate with 
prevention modeling in animal models of breast and bladder cancer examining the effects of erlotinib 
administered either continuous or intermittently (weekly). Studies from Lubet et al. (Lubet, submitted 
2013) have observed decreased Ki67 expression in response to weekly erlotinib in the MNU mouse breast 
cancer model as well as a significant decrease in phosphorylated ERK expression.  The limited clinical 
efficacy of EGFR inhibitors suggests that identification of resistance mechanisms may identify new 
pathways for targeting. Studies also showed that the extent of loss of E-cadherin was in associated with 
the depth of urothelial carcinoma invasion (Sun 2002), and that E-cadherin plays a central role in 
modulation of EGFR response in urothelial carcinoma (Black 2008).  Recent collaborative work 
involving extramural and intramural NCI-funded researchers examined the effects of gefitinib in a rat 
bladder cancer model suggested gefitinib exhibits its preventive efficacy on bladder tumorigenesis by 
upregulating let-7 and inhibiting the cell cycle (Lu 2011).  Cell culture study confirmed that the increased 
expression of let-7c decreases gefitinib-treated bladder tumor cell growth.  An identified hub gene, like 
let-7 may be able to serve as pharmacodynamic or efficacy biomarkers in clinical trials of 
chemoprevention in human bladder cancer.  Micro (mi)RNAs are emerging as important regulators of 
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carcinogenesis.  Let-7, a conserved family, regulates key differentiation processes during development. 
Loss of let-7 in cancer results in reverse embryogenesis and dedifferentiation (Peter 2009). Let-7 
alterations have been reported in various malignancies (Osada and Takahashi 2011, Childs 2009, 
Nadiminty 2012, Quesne 2012).  
 
In addition to the above biomarkers directly associated with erlotinib/EGFR, we will also examine 
expression of p53. Mutations of the p53 gene are the most common genetic defect in human tumors. The 
p53 gene functions as a tumor-suppressor gene and more specifically as a cell-cycle regulator.  Levels of 
p53 protein increase in response to damage to DNA, arresting the cell cycle and allowing time for the 
repair of DNA (Esrig 1994). P53 has been studied extensive in the past decade. Many studies showed that 
P53 overexpression was associated with bladder cancer progression (Shariat 2009, Sarkis 1993, 
Grossman 1998).  
 
Methodology Summary - For all protein marker detection and quantification a mask antibody – 
pancytokeratin (panCK) will be used to define the epithelial compartment including benign urothelium 
and urothelial tumor. A horse radish peroxidase (HRP) conjugated secondary antibody and Deep Space 
Black chromogen (DSP, Biocare Medical) will be used as the detecting system. A state-of-the art 
morphometrical system-Vectra™ (PerkinElmer) will be used for quantitation of the biomarkers. For 
miRNA detection (let-7 miRNA is located in the cytoplasm) and quantification a state-of -the-art 
technology – RNAscopeTM (Advanced Cell Diagnostics) will be used. This technology has a claimed 
sensitivity of detecting single copy of mRNA. Briefly, a cocktail of let-7 specific probes will be designed 
to detect let-7 from patient tissue samples and a HRP-labeled amplification system will be used for 
visualization (www.acdbio.com). Vectra system will be used to quantify let-7 miRNA expression in the 
cytoplasmic compartment of tumor and normal urothelium. (Please see Section 9 for details).  
 
Pharmacokinetics.  Pharmacokinetic parameters have been associated with erlotinib toxicity, an important 
consideration in chemoprevention trials and will be assessed as part of this trial (White-Koning 2011, Lu 
2006).  Erlotinib and its principal metabolite OSI-420 will be evaluated by high-performance liquid 
chromatography as previously described (Hamilton 2006).  
 
International Prostate Symptom Score (I-PSS).  Hyperplasia and inflammation are directly or indirectly 
linked to carcinogenesis.  Thusly, we are interested in prostatic hyperplasia.  Little is known about the 
role of EGFR in benign prostatic hyperplasia.  Recently, fibrosis has been implicated as a major player in 
benign prostatic hyperplasia (Ma 2012, Macoska 2012, Rodriguez-Nieves 2013).  Fibrosis of the urinary 
tract has largely been assessed in kidney disease (Chen 2012) and EGFR appears to be a key mediator of 
fibrosis.  However, less is known about the role of EGFR in fibrosis of the prostate and BPH.  Our 
unpublished findings have identified that when the EGFR ligand, TGF-alpha, is force expressed in mice, 
prostatic fibrosis and increased rates of lower urinary tract dysfunction ensue.  Additionally, we have 
demonstrated that EGFR-phosphorylation promotes collagen type 1 expression in prostatic stromal cells 
grown in vitro and the EGFR inhibitor, erlotinib, decreased prostatic collagen gene expression in these 
cells.  These preliminary findings suggest that EGFR inhibitors may positively affect lower urinary tract 
symptoms. 
 
As a part of our preliminary study of erlotinib in participants at risk of bladder neoplasia, we would like to 
perform an exploratory assessment of men randomized onto the study whether urination symptoms alter 
while on study.  A well documented survey (IPSS) of urination symptoms which correlates with prostatic 
hyperplasia in men will be filled out by men at baseline and end of study.   
 
8.3 
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All subjects will be off agent on or before day 28 of administration. Participants may stop taking study 
agent for the following reasons: completed the protocol-prescribed intervention, adverse event or serious 
adverse event that would compromise the surgery, inadequate agent supply, noncompliance, concomitant 
medications or medical contraindication. Being off agent does not imply being off study. Unless a patient 
meets the off study criteria in the next section, a patient will still be considered on study. 
 
8.4 
Off-Study Criteria 
 
Participants may go off study for the following reasons: the protocol intervention and any protocol 
required follow-up period is completed, AE/SAE, lost to follow-up, participant withdrawal, physician 
decision, protocol violation, or death. Off study will mean that the investigator will not be able to or does 
not need to follow the patient to complete any measurements. If the reason is reversible (e.g., lost to 
follow-up), a patient may be placed back on study. Unless a patient specifically requests it (which may or 
may not happen with a withdrawal of consent), even though a patient goes off study, available data will 
still be used for analyses subject to compliance and exclusion requirements (refer to section 13.4). 
 
8.5 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the investigation at any time. If not stopped 
early, the study will be considered terminated when the final report is written. The Consortium's data and 
safety monitoring board will be reviewing interim safety data, and will make recommendations as to 
study continuation after considering the safety data. 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Rationale for Methodology Selection 
Erlotinib Pharmacokinetics. Pharmacokinetic parameters have been consistently associated with erlotinib 
toxicity, an important consideration in chemoprevention trials and will be assessed as part of this trial. 
(White, 2011, Lu 2006) 
Blood samples will be collected prior to starting therapy, prior to dosing on day 8 (if available), and on 
the day of surgery, approximately day 16.  Erlotinib and its principal metabolite OSI-420 will be 
evaluated by high-performance liquid chromatography as previously described (Hamilton 2006).  
EGF receptor. EGF receptor (EGFR) is upregulated in most epithelial cancers where signaling through 
EGFR contributes to cancer cell proliferation and survival. The limited clinical efficacy of EGFR 
inhibitors suggests that identification of resistance mechanisms may identify new pathways for 
therapeutic targeting. E-Cadherin. Studies have shown that the extent of loss of E-cadherin was associated 
with the depth of urothelial carcinoma invasion (Sun 2002), and that E-cadherin plays a central role in 
modulation of EGFR response in urothelial carcinoma (Black 2008). Ki67. Antigen KI-67 is a nuclear 
protein that is associated with and may be necessary for cellular proliferation. Lubet et al. ( Lubet 2013 
submitted) observed decreased Ki67 expression in response to weekly erlotinib in the MNU mouse breast 
cancer model as well as a significant decrease in phosphorylated ERK expression. ERK. Extracellular 
regulated kinase (ERK) is an important downstream factor of EGFR in MAP kinase pathway. Its 
activation (phosphorylation) plays a key role in carcinogenesis and cancer progression of many cancers 
(Lujan 2010, Chou 2010)including urothelial carcinoma (Lee 2013, Ling 2011). Study showed that 
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Let 7. Micro (mi)RNAs are emerging as important regulators of cellular differentiation, their importance 
underscored by the fact that they are often dysregulated during carcinogenesis.  Let-7, a conserved family, 
regulates key differentiation processes during development. Loss of let-7 in cancer results in reverse 
embryogenesis and dedifferentiation (Peter 2009). Let-7 alterations have been reported in prostate and 
lung cancers and other malignancies (Osada and Takahashi 2011, Childs 2009, Nadiminty 2012, Quesne 
2012). P53. Mutations of the p53 gene are the most common genetic defect in human tumors. The p53 
gene functions as a tumor-suppressor gene and more specifically as a cell-cycle regulator.  Levels of p53 
protein increase in response to damage to DNA, arresting the cell cycle and allowing time for the repair of 
DNA (Esrig 1994). P53 has been studied extensive in the past decade. Many studies showed that P53 
overexpression was associated with bladder cancer progression Shariat 2009, Sarkis 1993, Grossman 
1998).  
 
Assay Performance: Immunohistochemistry (IHC) and Biomarker Quantitation (W. Huang, U of Wisc): 
Chromogenic multiplex IHC assay will be used, so the spatial variation of the biomarker expression in the 
tissue can also be analyzed and compared. Tissue slides will be deparaffinized and stained following 
standard protocol (Warren 2009, Huang 2009, Huang 2012). Target markers will be detected with specific 
antibodies. Horse radish peroxidase (HRP) conjugated secondary antibody and 3,3'-Diaminobenzidine 
(DAB) substrate, and  alkaline phosphatase conjugated secondary antibody and Warp red substrate 
(Biocare Medical, Concord, CA) will be used as detecting system. The Hematoxylin will be used as 
counterstain.  
 
Vectra™ (Caliper Life Sciences, Hopkinton, MA) will be used for quantitation of the biomarkers. This 
system includes an automated slide scanner and state-of-the-art softwares (NuanceTM and inFormTM). 
Vectra™ is the most advanced instrument for extracting proteomic and morphometric information from 
tissue microarray or intact tissue sections. Vectra merges automated slide-handling, multispectral imaging 
technology, and unique pattern-recognition-based image analysis into a powerful system for discovery 
and clinical studies. This system accurately measures protein or mRNA/DNA targets and morphometric 
characteristics in distinct tissue regions of interest on whole slides or tissue microarray (TMA). Sections 
can be labeled with either immunofluorescent (IF) or immunohistochemical (IHC) stains, or in situ 
hybridization (ISH) or with conventional stains such as H&E and trichrome. With IF or IHC or ISH, 
single or multiple proteins or mRNA/DNA targets can be measured on a per-tissue, per-cell, and per-cell-
compartment (eg. nuclear, cytoplasmic) basis, even if those signals are spectrally similar, are in the same 
cell compartment or are obscured by autofluorescence. Vectra™ processes up to 200 slides in a single run 
or analyze every spot in a TMA. Pathology Tissue Imaging Laboratory (PTI), directed by W. Huang, has 
been using the Vectra system for two years. The process to quantitate target proteins using the Vectra™ is 
briefly described as follows:   
 
Image acquisition: Briefly, the stained slides will be loaded onto the Vectra slide scanner. A scanning 
protocol including a spectral library will be created based on the tissue size, areas of interest and staining 
complexity (single or multiple staining in a single section). 8-bit image cubes will be acquired for 
analysis. For setting up the spectral library, three control prostate tissue slides with one dye only (DAB 
dye, Warp red and hematoxylin, respectively) will be prepared and scanned. 
 
Analysis: Each chromogen has its unique spectral characteristics (curve), which is the basis for building 
the spectral library. First, we will use the Nuance software and image cubes acquired from the control 
slides to create a spectral library – defining the spectral curve for each chromogen (DAB, Warp red and 
hematoxylin) used in this experiment. The spectral library will then be used to unmix the signals on the 
test slides triple-stained with DAB, Warp red and hematoxylin by recognizing their unique spectral curves 
for quantitation. By such, signal noises and cross-talk are eliminated (Figure 1). Then, using the created 
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cytoplasm) segmentations. Then the target signals will be quantitated within the selected subcellular 
compartment(s) of interest. Continuous signal intensity data will be generated. 
 
 
 
Endpoint-specific Methodology. 
 
For all protein marker detection and quantification:   
A mask antibody – pancytokeratin (panCK) will be used to define the epithelial 
compartment including benign urothelium and urothelial tumor. A horse radish peroxidase 
(HRP) conjugated secondary antibody and Deep Space Black chromogen (DSP, Biocare 
Medical) will be used as the detecting system. A state-of-the art morphometrical system-
Vectra™ (PerkinElmer) will be used for quantitation of the biomarkers. (Please see methodology 
p33-34 for details).  
 
Phosphorylated EGFR detection and quantification: Antibody specific for EGFR (anti-
EGFR, mouse monoclonal (mmAB), Abcam) and EGFR autophosphorylation (anti-EGFR 
phospho Y1092, rabbit monoclonal antibody (rmAb), Abcam) will be used to detect and 
quantitate EGFR and phosphorylated EGFR. A horse radish peroxidase (HRP) conjugated 
secondary antibody and 3,3'-Diaminobenzidine (DAB) substrate (brown), and an alkaline 
phosphatase conjugated secondary antibody and Warp red substrate (Biocare Medical, Concord, 
CA) will be used as the detecting system, respectively. So, totally three primary antibodies will 
be simultaneously stained and detected on patient tissue samples [cytokeratin AE1/AE3 (black), 
anti-EGFR(brown) and anti-EGFR phosphor (red].  Multispectral immunohistochemstry will be 
used to detect these two targets simultaneously. Hematoxylin will be used as counterstain. Since 
phosphorylated EGFR and EGFR are located on cell membrane including cytoplasmic 
membrane, endoplasmic reticulum membrane, Golgi apparatus membrane. nucleus 
membrane and endosome membrane. We will acquire quantitative measurement (mean 
optical density per pixel area) from tumor epithelium and adjacent normal urothelium. And then 
we will compare phophorylated EGFR expression levels in tumor to adjacent normal urothelium, 
and also compare the ratios of phosphorylated EGFR (detected by anti-EGFR phosphor, rmAb) 
to total EGFR (detected by anti-EGFR mmAb) in tumor and adjacent normal urothelium. 
 
Ki-67, p53 and E-cadherin detection and quantification: Antibodies specific for Ki-67, p53 and 
E-cadherin will be used to detection and quantitation. Three sets of double immunostaining will 
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(Biocare Medical). An alkaline phosphatase conjugated secondary antibody and Warp red 
substrate (Biocare Medical) will be used to detect the target antibodies (Ki-67, p53 and E-cad). 
Hematoxylin will be used as counterstain. Since Ki-67 and p53 are located in the nucleus and E-
cad is located in the cytoplasmic membrane, nuclear Ki-67 and p53 and membranous E-cadherin 
expression will be quantitated using Vectra system. 
 
Method for miRNA detection and quantification: 
Let-7 quantification: let-7 miRNA is located in the cytoplasm. A state-of -the-art technology – 
RNAscopeTM (Advanced Cell Diagnostics) will be used. This technology has a claimed 
sensitivity of detecting single copy of mRNA. Briefly, a cocktail of let-7 specific probes will be 
designed to detect let-7 from patient tissue samples and a HRP-labeled amplification system will 
be used for visualization (www.acdbio.com). Vectra system will be used to quantify let-7 
miRNA expression in the cytoplasmic compartment of tumor and normal urothelium. 
 
Erlotinib Pharmacokinetics (J Kolesar, U of Wisc): Blood samples will be collected prior to 
starting therapy, on day 8, and on the day of surgery (day 16).  Plasma will be separated by 
centrifugation and stored at -70C or colder until analysis.  Erlotinib and its principal metabolite 
OSI-420 will be evaluated by high-performance liquid chromatography as previously described 
(Hamilton 2006).  
 
9.2 
Comparable Methods 
 
For the analysis of erlotinib, both LCMSMS and HPLC assays are available methodologies.  LCMSMS is 
usually preferred over HPLC due to its improved sensitivity although both methods are standard for 
quantitative analysis of drug levels. For expression of tissue biomarkers the options of assessing message 
RNA or DNA levels exists in addition to gene product levels (protein expression). Our goal is to assess 
direct and indirect effects of erlotinib upon bladder urothelium and based on this goal and the 
convenience of examining protein expression from paraffin blocks or unstained slides, we have chosen 
protein expression (with the exception of let-7 which is microRNA expression).  The increased sensitivity 
and ability to also examine cellular localization of protein expression has led us to use the multispectral 
analysis of the VECTRA system rather than standard qualitative expression of macro or micro array 
immunohistochemistry. 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
The University of Wisconsin Comprehensive Cancer Center’s 3P Laboratory (Pharmacodynamics, 
Pharmacokinetics, Pharmacogenomics Lab) will serve as the central repository for all research specimens. 
The UWCCC 3P Laboratory will prepare sample kits for each subject enrolled on the study. Each site will 
receive one kit as they activate the study. The 3P lab will send additional kits to the sites as needed based 
on the rate of accrual. All tissue biomarkers will be done in the University of Wisconsin Translational 
Research in Pathology (TRIP) Laboratory under the direction of Wei Huang, MD (Study Pathologist). 
 
10.2 
Collection and Handling Procedures 
 
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At each pharmacokinetic time point draw one 3ml green top tube. Centrifuge the tube for 10 minutes to 
separate plasma.  Divide the plasma into 2 cryovial tubes.  Label the 2 cryovial tubes with the labels 
provided in the kit.  Make sure to add the participant number, initials,  date, and hour: minute of the 
pharmacokinetic blood draw  to the labels.  Freeze the cryovial tubes at –70°C, and save for transport to 
the UWCCC 3P Laboratory.  The 3P Laboratory has purchased a software system to track samples. 
10.2.2 Tissue Handling: 
 
Biopsy tissues will be sent to Surgical Pathology for routine fixation, processing and embedding. Each 
site will provide tissue blocks of normal appearing bladder urothelium adjacent to tumor and tumor OR 
10 unstained slides representing normal appearing bladder urothelium adjacent to tumor and 10 unstained 
slides representing tumor tissue (when available). 
 
10.3 
Shipping Instructions 
10.3.1 Shipping to UWI 
 
Once a patient has completed the study and all laboratory samples have been collected, ship the carton 
containing all of the samples for one patient to the address below.  If multiple patients are completing the 
study, samples from multiple patients can be combined in one shipment. 
 
3P Lab 
K4/559 CSC, 600 Highland Avenue 
Madison, WI 53792-5666 
 
Call the 3P Lab to inform them of a shipment (608) 263-5369 or email the 3P lab mailing list 
3plab@lists.medicine.wisc.edu  
 
Use the express courier service indicated by the shipping label contained in the kit.  Closely follow all 
special shipping instructions outlined in the kit instruction packet. 
 
Ship only on Monday, Tuesday or Wednesday to ensure safe arrival during the week. Do not ship the day 
before a holiday. 
 
Fill the styrofoam cooler with dry ice and put all of the blood samples into the cooler.  Place the cooler 
into the shipping box in which you received the kit.  
 
10.4 
Tissue Banking 
 
Biologic specimens collected during the conduct of each clinical trial that are not used during the course 
of the study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the Contractor shall collect, verify and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense. 
 
11. 
REPORTING ADVERSE EVENTS  
 
DEFINITION: An adverse event (AE) is any untoward medical occurrence in a study participant. An AE 
does not necessarily have a causal relationship with the treatment or study participant. An AE can 


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therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or 
disease temporally associated with participation in a study, whether or not related to that participation. 
This includes all deaths that occur while a participant is on a study. 
 
A list of adverse events that have occurred or might occur (Reported Adverse Events and Potential Risks) 
can be found in Section 6.2, Pharmaceutical Information as well as the Investigator Brochure. 
 
11.1 
Adverse Events 
 
11.1.1 Reportable AEs 
 
All AEs that occur after the informed consent is signed and baseline assessments are completed 
(including run-in) must be recorded on the AE CRC (paper and/or electronic) whether or not related to 
study agent. 
 
11.1.2 AE Data Elements: 
 
The following data elements are required for adverse event reporting. 
• 
AE verbatim term 
• 
System Organ Class (SOC) 
• 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) AE term 
• 
Event onset date and event ended date 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a serious adverse event (SAE) 
• 
Whether or not the subject dropped due to the event 
• 
Outcome of the event 
 
11.1.3  Severity of AEs 
 
 
 
11.1.3.1 
Identify the AE using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. The CTCAE provides descriptive terminology and a grading scale for each adverse 
event listed. A copy of the CTCAE can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AEs will be assessed according to the CTCAE grade associated with the AE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v4.0. as stated below.  
 
CTCAE v4.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
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Grade 
Severity 
Description  
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
 
ADL 
 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
11.1.4 Assessment of relationship of AE to treatment 
 
The possibility that the adverse event is related to study agent will be classified as one of the following: 
not related, unlikely, possible, probable, definite. 
 
11.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will 
be followed according to good medical practices and documented as such. 
 


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11.2 
Serious Adverse Events  
 
11.2.1 DEFINITION: Fed. Reg. 75, Sept. 29, 2010 defines SAEs as those events, occurring at any dose, 
which meet any of the following criteria: 
• 
Results in death 
• 
Is life threatening (Note: the term life-threatening refers to an event in which the patient was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Is a congenital abnormality/birth defect 
• 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed. 
 
11.2.2 Reporting SAEs to DCP 
 
11.2.2.1 The Lead Organization and all Participating Organizations will report SAEs on the DCP  
form found at http://prevention.cancer.gov/files/clinical-trials/SAE_form.doc. 
 
11.2.2.2 Contact the DCP Medical Monitor by phone within 24 hours of knowledge of the event.  
 
Howard Parnes, MD 
Prostate and Urologic Cancer Research Group 
Division of Cancer Prevention, National Cancer Institute, NIH, DHHS 
Shady Grove Campus 
9609 Medical Center Dr., Suite 5E-302 
Rockville, MD 20850 
parnesh@mail.nih.gov 
(240) 276-7045 
 
Include the following information when calling the Medical Monitor: 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
Name of reporter 
• 
Call back phone number 
• 
Affiliation/Institution conducting the study 
• 
DCP protocol number 
• 
Title of protocol 
• 
Description of the SAE, including attribution to drug and expectedness 
 
11.2.2.3 The Lead Organization and all Participating Organizations will FAX written SAE reports to the 
DCP Medical Monitor within 48 hours of learning of the event using the paper SAE form. The written 
SAE reports will also be Faxed (650-691-4410) or emailed (safety@ccsainc.com) to DCP’s Regulatory 
Contractor, CCS Associates (phone: 650-691-4400). 
 
 
 


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11.2.2.4 The DCP Medical Monitor and regulatory staff will determine which SAEs require FDA 
submission. 
 
11.2.2.5 The Lead Organization and all Participating Organizations will comply with applicable 
regulatory requirements related to reporting SAEs to the IRB/IEC.  
 
11.2.3 Follow-up of SAE 
 
Site staff should send follow-up reports as requested when additional information is available. Additional 
information should be entered on the DCP SAE form in the appropriate format. Follow-up information 
should be sent to DCP as soon as available.  SAEs related to study agent will be followed until resolution. 
 
12. 
STUDY MONITORING 
 
12.1 
Data Management 
 
All of the procedures outlined in the University of Wisconsin Chemoprevention Consortium standardized 
Data Management Plan (DMP approval 6/3/2013) will be followed in this protocol. There are no 
supplementary Data Management procedures for this protocol.  
 
This study will report clinical data using the CLO database OnCore which is a web-based clinical 
trials/database. OnCore will be the database of record for the protocol and subject to NCI and FDA audit. 
All OnCore data entry will be performed at the CLO where staff is trained in OnCore per our DMP and 
applicable regulatory requirements such as 21 CFR; Part 11. 
 
In order to standardize the collection of information, the CLO will provide POs with preprinted study-
specific source documents. 
 
12.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific case report forms (CRF) developed from the 
standard set of DCP Chemoprevention CRF Templates and utilizing NCI-approved Common Data 
Elements (CDEs). The approved CRFs will be used to create the electronic CRF (eCRF) screens in 
OnCore. CLO staff will enter data into OnCore and transfer to Federal Security Compliant formats for 
transmission to DCP according to pre-established DCP standards and procedures. Amended CRFs will be 
submitted to the DCP Protocol Information Office for review and approval. 
 
12.3 
Source Documents 
 
All data reported on CRFs must be documented on separate source documents found in the subject’s 
medical record. The CLO will provide participating sites with standardized, pre-printed source documents 
that may be used to help ensure that all data items are collected. Participating sites are discouraged from 
using the CRFs for source documentation. If this practice occurs, the CRFs used as source documents 
must be signed and dated on the date of contact and a copy of the CRFs must be placed in the medical 
record as well as the research chart. 
 


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12.4 
Data and Safety Monitoring Plan 
 
The standard University of Wisconsin Chemoprevention Consortium DSMP was approved by the DCP on 
9/14/2005. The UW Chemoprevention Consortium Data and Safety Monitoring Committee meet every 6-
12 months to review all data from ongoing consortium studies. Members review pooled, unblinded safety 
data to assess ongoing human subjects safety. 
 
12.5 
Sponsor or FDA Monitoring 
 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies and records to review and verify data pertinent to the study.  
 
12.6 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
IRB records and other regulatory documentation will be retained by the Investigator in a secure storage 
facility in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of 
Human Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, 
and NCI/DCP requirements. The records for all studies performed under an IND will be maintained, at a 
minimum, for two years after the approval of a New Drug Application (NDA). For NCI/DCP, records 
will be retained for at least three years after the completion of the research. NCI will be notified prior to 
the planned destruction of any materials. The records will be accessible for inspection and copying by 
authorized persons of the Food and Drug Administration.  
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
 
This section is not applicable for this study agent.  The agent will be purchased by NCI. 
 
12.7.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational agents contain confidential 
information and should not be shared or distributed without the permission of the NCI. If a patient 
participating on the study or participant’s family member requests a copy of this protocol, the individual 
should sign a confidentiality agreement. A suitable model agreement can be downloaded from the DCP 
website. 
 
12.7.2 For a clinical protocol where there is an Investigational Agent used in combination with (an) 
other investigational Agent(s), each the subject of different collaborative agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-party Data”). 
 
12.7.3 NCI must provide all Collaborators with prior written notice regarding the existence and nature of 
any agreements governing their collaboration with NIH, the design of the proposed combination protocol, 
and the existence of any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 


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12.7.4 Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain 
regulatory approval, or commercialize its own investigational agent. 
 
12.7.5 Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational agent. 
 
12.7.6 Clinical Trial Data and Results and Raw Data developed under a collaborative agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate. All data made 
available will comply with HIPAA regulations. 
 
12.7.7 When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators of Collaborator's wish to contact them. 
 
12.7.8 Any manuscripts reporting the results of this clinical trial must be provided to DCP for immediate 
delivery to Collaborator(s) for advisory review and comment prior to submission for publication. 
Collaborator(s) will have 30 days (or as specified in the CTA) from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in 
order to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to DCP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to DCP prior to release. Copies of any 
manuscript, abstract, and/or press release/ media presentation should be sent to: 
 
 
Head, DCP Protocol Information Office 
 
 
E-mail: NCI_DCP_PIO@mail.nih.gov 
 
The Protocol Information Office will forward manuscripts to the DCP Project Officer for distribution to 
the Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/proprietary information. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
This is a Phase IIa randomized, placebo-controlled, double-blind cancer chemoprevention trial of 
modulation of EGFR phosphorylation and other intermediate endpoint biomarkers by intermittent 
erlotinib in subjects with bladder cancer.  Because there is a potential for a number of patients to be 
placed on a reduced dose of 300 mg/week because of intolerance to drug due to acne, in order to retain 
sufficient accrual at the 600 mg dose level, participants will be randomized in a 1:2 ratio of placebo to 
600mg erlotinib administered weekly for 3 doses with the last dose approximately 24 hours of TURBT or 
cystectomy. 
 
The primary endpoint for modulation of intermediate endpoint biomarkers will be the EGFR 
phosphorylation in normal appearing bladder epithelium adjacent to tumor 9-18 hours post-study dose; it 
is hypothesized that erlotinib will inhibit EGFR phosphorylation. 
 


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The secondary endpoints as prioritized include tolerance of high dose weekly erlotinib compared to 
placebo, EGF receptor phosphorylation in neoplastic bladder epithelium 9-18 hours post-study dose, the 
expression of e-cadherin and Ki67, the expression of phosphorylated ERK in normal and abnormal 
urothelium, limited pharmacokinetics of weekly erlotinib, the expression of p53 in normal and abnormal 
urothelium, and the expression of let-7 in normal and abnormal urothelium. 
 
The primary analysis will be an as-randomized comparison of EGFR phosphorylation in bladder 
epithelium between the two randomized arms, based on two-sample t-test with normalizing 
transformation if necessary or Wilcoxon rank-sum test. 
 
13.2 
Randomization and Stratification 
 
Randomization will be in a ratio of 1:2 in Placebo (4 tablets): erlotinib (4 tablets) by mouth once weekly, 
based on a permuted block of size 3 with stratification by planned use of agents that significantly decrease 
Erlotinib bioavailabiltity (tobacco, protein pump inhibitors) and by planned surgery (TURBT vs. 
cystectomy).    The decision was made not to stratify by site to avoid problems with sparse data. After 
random permutation of numbers from 1 to 3 in each block, incoming subjects in sequence will be 
randomized to treatment corresponding to the permuted numbers in sequence according to the following: 
placebo for number 1, and erlotinib for numbers 2 and 3. This process will be repeated after every 3 
subjects. 
 
13.3 
Sample Size and Feasibility  
 
The sample size for each group is based on comparing EGFR phosphorylation in bladder epithelium as 
measured by quantitative Vectra assay analysis of expression between the erlotinib and placebo arms.  
This primary endpoint can be considered a continuous random variable.  The sample size justification is 
thus based on a two-tailed two-sample t-test of the difference between the two groups at a significance 
level of 0.05.  In order to detect an effect size of 1, i.e. the difference in the mean change between the 
placebo arm and the erlotinib arm of 1 standard deviation, with power 0.85, the trial requires an effective 
sample size of 14 in the placebo arm and 28 in the erlotinib arm.  Assuming a random drop-out of up to 
5%, 15 subjects in the placebo arm and 30 subjects in the erlotinib arm will be enrolled for a total of 45 
subjects for this exploratory study. 
 
There will be six sites participating in the study.  Each randomized patient will be treated with study 
medication weekly x 3 doses.  We will allow for study duration of approximately 3 years. 
 
13.4 
Primary Objective 
 
The primary objective is 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 weekly as compared to placebo. The primary endpoint of the study is 
EGFR phosphorylation in bladder epithelium at the end of study (weekly for 3 doses) in subjects with 
bladder cancer.  For the primary comparison the difference between the placebo group and the erlotinib 
group will be tested as-randomized using a two-sample t-test with normalizing transformation if 
necessary or Wilcoxon rank-sum test. 
 
Because of the required dose modification to 300 mg for grade 2 rash or diarrhea and allowed dose 
modification for grade 1 rash/diarrhea if subject prefers (refer to section 5.6) there is the potential for a 
number of patients to reduce dose at some point in the study.  In addition, prior research has shown that 
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erlotinib better, but gaining fewer benefits, effectively receiving a reduced dose compared to non-smokers 
and those that are not taking proton pump inhibitors (refer to section 2).  As a supporting analysis for the 
primary endpoint we will explore a relationship for EGFR phosphorylation with a measure of dose 
received, and accounting for smoking status and proton pump inhibitor use.  
 
13.5 
Secondary Objectives 
 
For the secondary objectives, we will determine whether skin toxicity is present when erlotinib is 
administered weekly at 600 mg for weekly for 3 doses. We will determine if there is a difference in EGFR 
phosphorylation in neoplastic bladder epithelium 9-18 hours post-study dose between subjects 
randomized to erlotinib weekly versus placebo.  We will assess erlotinib plasma concentrations in 
subjects taking erlotinib weekly.   We will test for differences between arms in expression of 
phosphorylated ERK in normal and abnormal urothelium.  We will examine limited pharmacokinetics of 
weekly erlotinib.  We will determine, for normal, neoplastic tissue, and the difference between normal 
and neoplastic tissue, if there is a difference in the following markers of EGFR: e-cadherin, Ki-67 and p-
ERK, p53, and let-7 micro RNA. 
 
For secondary objectives, all measurements and changes in measurements of interest will be summarized 
by treatment arm (and, if applicable, by visit) with appropriate descriptive statistics.  Compliance, in 
terms of the number of pills missed, will be summarized by treatment arm with descriptive statistics, and 
tested for imbalance using Wilcoxon rank-sum test.  Patient toxicity throughout the study will be 
summarized in several ways; the presence or absence of any toxicity, worst CTCAE grade, and strongest 
investigator-defined relationship will all be examined and characterized by treatment arm, and analyzed 
appropriately (Wilcoxon rank-sum for ordinal data, Fisher’s exact test for dichotomous data, and log rank 
test for time to event data).  For tissue biomarkers, we will examine the differences between the groups 
for biomarkers in normal and neoplastic tissue, and the difference between normal and neoplastic tissue at 
the time of surgery;  (also, for those with available paired tissue samples we will examine pre to post 
change) with the appropriate tests; for dichotomous data we will use Fisher’s exact test, for ordinal data 
we will use Wilcoxon rank-sum test, and for continuous data, and a two-sample t-test with normalizing 
transformation if necessary or Wilcoxon rank-sum test. 
 
13.6 
Reporting and Exclusions 
 
As the nature of this study is exploratory, intent-to-treat should not be used as a principal analysis criteria.  
Nevertheless, no subjects will be excluded from the analysis and reporting, except for obvious random 
dropouts and for those who never took the protocol treatment.  
 
Compliance with the protocol treatment will be measured in the form of pill counts; the information will 
not be used for the primary analysis, but for the analysis supporting the primary endpoint. There will be 
no imputation of missing data for both the primary and the secondary endpoints. 
 
13.7 Evaluation of Toxicity 
 
All participants receiving any protocol treatment will be evaluated for toxicity from the time of their first 
dose of placebo or erlotinib up to the time of surgery according to the NCI's Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.  After the surgery the participants will be followed for 
seven to fourteen days for adverse events that are possibly, probably or definitely related to study drug. 
Serious Adverse Events (SAEs) related to study agent will be followed until resolution. Any adverse 
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drug will be followed after surgery until resolved or for 3 months, whichever is sooner. Adverse events 
that do not resolve should be referred to the participant’s primary care provider. 
 
13.8 Evaluation of Outcome/Endpoints 
 
For the primary analysis comparing EGFR phosphorylation across the treatment groups, the as-
randomized analysis will be used. All of the participants who met the eligibility criteria, with the 
exception of those who did not receive study agent, will be included in the main analysis. Random 
dropouts will be excluded.  
 
13.9 Interim Analysis 
 
Interim analysis will be performed at a regular schedule to document study progress and to review safety 
data. This will be performed by an unblinded statistician who is not connected with the day-to-day 
operation of the study; the regular study staff will not be unblinded. There is no plan for interim analysis 
for efficacy data. Results of interim analyses of safety data will be reported to the Consortium's data and 
safety monitoring board for review at approximately six month intervals. They will be in charge of 
reviewing safety information, including adverse events, serious adverse events, and death data, and 
making a judgment as to the advisability of continuation. There will be no hard and fast criteria set for the 
safety analysis.  
 
13.10 Ancillary Studies 
 
No ancillary studies are planned.  
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 
Form FDA 1572 
 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) 
will provide a signed Form FDA 1572 stating that the study will be conducted in compliance with 
regulations for clinical investigations and listing the investigators, at each site that will participate in the 
protocol. All personnel directly involved in the performance of procedures required by the protocol and 
the collection of data should be listed on Form FDA 1572. 
 
14.2 
Other Required Documents 
 
14.2.1 Signed and dated current (within two years) CV or biosketch for all study personnel listed on the 
Form FDA 1572 and Delegation of Tasks form for the Lead Organization and all Participating 
Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and 
Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 
for the Lead Organization and all Participating Organizations. 
 


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14.2.4 Documentation of training in “Protection of Human Research Subjects” for all study personnel 
listed on the FDA Form 1572 and Delegation of Tasks form for the Lead Organization and all 
Participating Organizations. 
 
14.2.5 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all 
Participating Organizations. 
 
14.2.6 Signed Investigator’s Brochure/Package Insert acknowledgement form 
 
14.2.7 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by 
the Principal Investigator for each site and initialed by all study personnel listed on the form 
 
14.2.8 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form 
FDA 1572 for the Lead Organization and all Participating Organizations 
 
14.3 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the 
Participating Organization(s) must obtain written approval to conduct the study from the appropriate IRB. 
Should changes to the study become necessary, protocol amendments will be submitted to the DCP PIO 
according to DCP Amendment Guidelines. The DCP-approved amended protocol must be approved by 
the IRB prior to implementation 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the IRB-approved Informed Consent to review. 
The investigator will explain all aspects of the study in lay language and answer all questions regarding 
the study. If the participant decides to participate in the study, he/she will be asked to sign and date the 
Informed Consent document. The study agent(s) will not be released to a participant who has not signed 
the Informed Consent document. Subjects who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option may be included within the informed consent document 
or may be provided as an addendum to the consent. A Model Consent Form for Use of Tissue for 
Research is available through a link in the DCP website. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, 
the Consortium Lead Organization, and the IRB at each Organization at which the protocol will be 
implemented. Any subsequent changes to the informed consent must be approved by NCI, DCP, the 
Consortium Lead Organization’s IRB, and then submitted to each organization’s IRB for approval prior 
to initiation. 
 
14.5 
Submission of Regulatory Documents 
 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for 
completeness and accuracy. Once the Consortia Lead Organization has received complete and accurate 
documents from a participating organization, the Consortium Lead Organization will forward the 
regulatory documents to the DCP Regulatory Contractor: 


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Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates 
 
1923 Landings Drive 
 
Mountain View, CA 94043 
 
Phone: 650-691-4400 
 
Fax: 650-691-4410 
 
 
E-mail Submissions: 
 
regulatory@ccsainc.com 
 
Regulatory documents that do not require an original signature may be sent electronically to the 
Consortium Lead Organization for review, which will then be electronically forwarded to the DCP 
Regulatory Contractor. 
 
14.6 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
All laboratory tests and clinic visits required for study participation will be done at no cost to the 
participant or his/her insurance company. The cost of the cystectomy or TURBT and all follow-up visits 
post-operatively will be the responsibility of the subject or insurer. Although it is not expected, taking 
part in this study may lead to added costs to participants. 
 


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REFERENCES 
 
Antoniewicz AA, Paziewska A, Mikula M, Goryca K, Dabrowska M, Poletajew S, Borowka A, 
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APPENDIX A 
 
Performance Status Criteria 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
0 
Dead. 
 


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APPENDIX B 
 
Information on Erlotinib (Study Drug) 
 
Erlotinib 
(Tarceva) 
 
Description 
Erlotinib is a medication used in the treatment of some cancers.  This study is being done to determine the 
potential cancer prevention effects in bladder tissue when erlotinib is taken once a week, and to determine 
how well people tolerate taking erlotinib once a week.  Erlotinib needs to be taken on an empty stomach, 
which means taking it at least 2 hours after you last ate something one hour before you next eat 
something. 
 
How It Is Given 
This medicine is a pill that you swallow. 
 
When to call us:  We would like to know if you experience any rash or diarrhea that continues for over 
24 hours.  We would also like to know if you experience any unexplained, persistent cough, fever, or 
shortness of breath immediately. 
 
Common Side Effects When Taken Daily: 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving erlotinib, more than 20 may have: 
• Rash  
• 
Diarrhea  
• 
Loss of appetite 
• 
Tiredness or fatigue 
• 
Shortness of breath 
• 
Cough 
• 
Nausea 
• 
Infection 
• 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving erlotinib, from 4 to 20 may have: 
• Sores in mouth 
• 
Itching 
• Acne 
• Dry skin 
• Weight loss 
• Irritation (redness, swelling, warmth, and pain) or infection of the skin around 
fingernails or toenails 
• Eye infection/pink eye 
• Dry eyes 
• 
Stomach pain or pain in the abdomen (belly) 
• 
Red bumps on the skin that are red, sore, and possibly infected  
 
 
 
 
 
POSSIBLE, SOME MAY BE SERIOUS 
The frequency of some individual side effects for people receiving erlotinib has not yet been 
determined: 
• Shoulder pain 
• Change in urine color 
• Indigestion 
• Gas in the belly, burping 
• Irritability (easily annoyed or made angry) 
• Swelling of the face, hands, feet or ankles 
• Runny nose 
• Dizziness 
• 
Headache 
• 
Blood clot in the lung which may cause pain, shortness of breath 
• 
Stroke (Stoppage of blood flow to your brain which may cause paralysis, weakness, 
headache) 
• 
Death or injury to unborn baby 
• 
Because of the potential harm to the infant, women should be advised against breast-
feeding while receiving erlotinib therapy 
 
 
 
 
 
 
 
 


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RARE, SOME MAY BE SERIOUS 
In 100 people receiving erlotinib, 3 or fewer may have: 
     Although very rare, some of the side effects listed below can cause death 
• Abnormal laboratory result which may indicate liver damage 
• Liver damage 
• Kidney damage which may cause swelling, may require dialysis 
• Swelling, irritation, or scarring of the lungs, which may cause pain or difficulty 
breathing.  
• A tear or hole in the stomach that may require surgery. More common in people with 
ulcers (sores in the stomach), diverticulitis (redness, pain, and swelling of part of the 
belly), and in people who take some types of drugs (NSAIDS, corticosteroids, 
chemotherapy). Talk to your study doctor about drugs to avoid.  
• Severe blistering or peeling of the skin 
• Patches of skin may become darker in color 
• Redness, swelling, sores, or a tear or hole in eye which may cause pain or blurred 
vision. 
• Increased bleeding (Internal bleeding, nose bleed). More common in people who take 
blood thinning drugs.  
• Increased body hair growth, hair loss, eyelash/eyebrow changes, or brittle/loose 
fingernails or toenails 
• Severe diarrhea or vomiting can cause an imbalance of minerals in the blood (called 
electrolytes) such as low potassium, with symptoms that may include weakness, 
fatigue, muscle cramps, or constipation. 
• 
In people with cancer of the pancreas who took combined treatment of erlotinib plus 
gemcitabine: heart attack, stroke, decreased red blood cells (anemia) which may cause 
tiredness, or may require blood transfusion, and decreased platelets which may cause easy 
bleeding, or longer bleeding. 
 
 
Special Concerns 
Erlotinib can interact with some kinds of antibiotics, antiviral, and antifungal drugs, and warfarin (a blood 
thinner).  You should make sure you have told your cancer doctor about all medicines you are using, and 
make sure your local doctor knows you are taking erlotinib if they prescribe any new ones. 


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Appendix C 
International Prostate Symptom Score (I-PSS)-Men Only 
PID:_________________  Date of birth:_________________Date completed_____________________ 
In the past 
month: 
Not 
at 
All 
Less than 
1 in 5 
Times 
Less than 
Half the 
Time 
About 
Half 
the 
Time 
More 
than Half 
the Time 
Almost 
Always 
Your 
score 
1. Incomplete Emptying 
How often have you had 
the sensation of not 
emptying your bladder? 
0 
1 
2 
3 
4 
5 
2. Frequency 
How often have you had 
to urinate less than every 
two hours? 
0 
1 
2 
3 
4 
5 
3. Intermittency 
How often have you found 
you stopped and started 
again several times when 
you urinated? 
0 
1 
2 
3 
4 
5 
4. Urgency 
How often have you found 
it difficult to postpone 
urination? 
0 
1 
2 
3 
4 
5 
5. Weak Stream 
How often have you had 
a weak urinary  stream? 
0 
1 
2 
3 
4 
5 
6. Straining 
How often have you had 
to strain to start urination? 
0 
1 
2 
3 
4 
5 
None 
1 Time 
2 Times 
3 Times 
4 Times 
5 Times 
7. Nocturia 
How many times did you 
typically get up at night 
to urinate? 
0 
1 
2 
3 
4 
5 
Total I-PSS 
SScore: 
1-7: Mild 
8-19: Moderate 
20-35: Severe 
Quality of Life Due to Urinary 
Symptoms 
 
Delighted 
 
Pleased 
 
Mostly 
Satisfied 
 
Mixed 
 
Mostly 
Dissatisfied 
 
Unhappy 
 
Terrible 
 
If you were to spend the rest of your life 
with your urinary condition just the way it 
is now, how would you feel about that? 
0 
1 
2 
3 
4 
5 
6 


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About the I-PSS 
The International Prostate Symptom Score (I-PSS) is based on the answers to seven questions 
concerning urinary symptoms and one question concerning quality of life in men.  Each question 
concerning urinary symptoms allows the patient to choose one out of six answers indicating increasing 
severity of the particular symptom.  The answers are assigned points from 0 to 5.  The total score can 
therefore range from 0 to 35 (asymptomatic to very symptomatic). 
 
The questions refer to the following urinary symptoms: 
 
Questions 
Symptom 
1 
Incomplete emptying 
2 
Frequency 
3 
Intermittency 
4 
Urgency 
5 
Weak Stream 
6 
Straining 
7 
Nocturia 
 
Question eight refers to the patient’s perceived quality of life. 
 
The first seven questions of the I-PSS are identical to the questions appearing on the American 
Urological Association (AUA) Symptom Index which currently categorizes symptoms as follows: 
 
Mild (symptom score less than or equal to 7) 
Moderate (symptom score range 8-19) Severe 
(symptom score range 20-35) 
 
The International Scientific Committee (SCI), under the patronage of the World Health Organization 
(WHO) and the International Union Against Cancer (UICC), recommends the use of only a single 
question to assess the quality of life.  The answers to this question range from “delighted” to “terrible” 
or 0 to 6.  Although this single question may or may not capture the global impact of benign prostatic 
hyperplasia (BPH) Symptoms or quality of life, it may serve as a valuable starting point for a doctor-
patient conversation. 
 
The SCI has agreed to use the symptom index for BPH, which has been developed by the AUA 
Measurement Committee, as the official worldwide symptoms assessment tool for patients suffering 
from prostatism. 
 
The SCI recommends that physicians consider the following components for a basic diagnostic 
workup: history; physical exam; appropriate labs, such as U/A, creatinine, etc.; and DRE or other 
evaluation to rule out prostate cancer. 
 
 
 
 
 
 


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Research Subject Information and Consent Form 
 
Study Title for Participants:  Testing erlotinib to prevent bladder cancer in 
people with bladder cancer 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  
UWI2013-01-02 Phase II Clinical Chemoprevention Trial of Weekly Erlotinib  
Before Bladder Cancer Surgery 
 
Invitation/Summary 
 
We would like to invite you to participate in this clinical trial, a research study that we hope will 
help us learn more about how to prevent bladder cancer in people who are at risk for that kind of 
cancer.  You are being asked to take part in this study because you have been diagnosed with or 
are suspected of having a cancerous tumor in your bladder which your doctor plans to remove 
with surgery.  Your doctor and the research study staff will explain this study to you and answer 
any questions you might have about it.  Participation is voluntary.  Please take your time to make 
your decision about whether or not you want to participate.  You may want to discuss this with 
your family, friends or other members of your health care team.  Please feel free to contact us 
with any questions or concerns you might have.  
 
Why is this study being done? 
 
We are doing this study to determine the potential cancer prevention effects in bladder tissue of 
once a week erlotinib and how well tolerated erlotinib is once a week.  In this study, you will get 
either erlotinib or placebo. There will be a total of about 45 people taking part in this study 
nationally and about insert number people will be enrolled here at the insert study site. 
 
 
Definitions: 
 
Erlotinib (also known as Tarceva) is an anticancer medication.  It blocks the action of an 
abnormal protein that tells cells in the body to multiply more than they should.  When cells 
multiply more than they should, they form a growth called a tumor.  Erlotinib is a Human 
Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor 
(HER1/EGFR) tyrosine kinase inhibitor. 
 
 
Placebo is something that is made to look like a treatment or medicine but has no real medicine 
in it.  In this study, placebo will be tablets that look just like erlotinib but don’t have 
erlotinib or any medicine at all in them.   
 
What are my other choices if I do not take part in this study?  
 
The choice is yours.  If you decide not to take part in this study, you do have other choices. For 
example: 


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• 
You may choose to have the surgery and any other standard treatments 
recommended by your doctor and not participate in this study. 
•    You may choose to take part in a different study, if one is available.  
• Or you may choose to do nothing. 
 
What are the study groups? 
 
This study has two study groups.  
 
Group 1 will receive the study drug erlotinib.  
Group 2 will receive a placebo.  
 
You will be randomly put into one of the two study groups.  Being randomly put into a group is 
like a coin toss that is done by a computer.  We do this because no one knows if one study group 
is better, the same, or worse than the other group. Once you are put in a group, you cannot switch 
to the other group. Neither you nor your doctor will know if you are receiving the erlotinib or the 
placebo. Your doctor cannot choose which group you will be in.  
 
For every two people who are put into the erlotinib group, one person will be put into the 
placebo group.  This means that you have about a 70% chance of being in the erlotinib group 
versus the placebo group. 
 
 
 
 
 
 
Grou2 
 
 
How long will I be in this study? 
 
You will receive the study drug weekly for 3 doses before your bladder surgery.  If that 
procedure is delayed for some reason, you could receive one additional weekly treatment but that 
is the most you could receive.  Even if you do not finish the study, your doctor will continue to 
watch you for side effects and follow your condition for 7-14 days after your surgery.  The 
duration of study participation is 4-6 weeks. 
 
What extra tests and procedures will I have if I take part in this study? 
 
In addition to the exams, tests, and procedures you will have as part of the usual approach for 
your condition, there are some extra tests and procedures that you will need to have if you take 
part in this study. 
 
Before you begin the study you will have a screening/baseline visit.   
You agree to 
take part in this 
study 
Randomize 
(The computer randomly 
puts you in a study group) 
Group 1 
Erlotinib 
Group 2 
Placebo 


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At this visit the following extra tests and procedures will be done to find out if you can be in the 
study. If you have already had any of these tests done as part of your regular medical care within 
30 days of starting the study medicine we may be able to use those results: 
 
• 
Medical History: A doctor or nurse from the study will ask you about any health 
problems, surgeries or treatments you had in the past and any health problems or 
symptoms you are having now.  We will also ask you about any medicines you are 
taking and about your smoking history. 
• 
Physical Exam and Vital Signs: A doctor or nurse from the study will do an exam and 
measure your height, weight, blood pressure, pulse and temperature.  
• 
The lead study doctor is interested in seeing if the study medicine improves urine 
difficulty in men.  The study staff will ask men to fill out a survey about their urinary 
symptoms before they take the study medicine and after they take the study medicine 
• 
Because the effects of erlotinib on the developing human fetus are unknown, if you 
are a woman of childbearing potential, we will do a urine or serum pregnancy test at 
your Baseline Visit to make sure that you are not pregnant.  In addition both 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. 
• 
Blood Tests: About 2 tablespoons of blood will be taken with a needle from a vein in 
your arm.   
• 
Most of this blood will be sent to the hospital or clinic lab and will help us 
find out if your health is well enough for you to participate in this study. 
• 
About 1/3 tablespoon of this blood will be used to help us learn more about 
how the study drug will work in your body.   
 
If you are determined eligible for the study and agree to proceed with receiving the study drug 
you will be given two additional medications: topical clindamycin which is an antibiotic gel; and 
topical hydrocortisone which is an anti-inflammatory cream to be used in case a rash develops 
(the rash is described in the section of this consent under “What risks can I expect from taking 
part in this study?”). 
 
Taking the Study Medicine: 
 
If these exams, tests, and procedures show that you can take part in the study, and you choose to, 
we will order study medicine for you.  It will arrive in just a couple of days.  You can return to 
pick up your study medicine or we can send it to you by UPS or FedEx overnight delivery.   
 
The tablets in your bottle of study medicine will contain either erlotinib or placebo.  You will 
take the study medicine only 1 time per week for 3 doses before your surgery.  You will take 
your last dose on the day before your surgery. Along with your study medication, you will be 
given a calendar.  The calendar will help remind you when and how to take your study medicine.  
We will ask you to write down the date and time you take your study medicine and to make a 
note of any symptoms, side effects or health changes you experience. 


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The study medicine needs to be taken on an empty stomach (at least 2 hours after you last ate 
something and one hour before you next eat something). We ask that you take your medicine in 
the evening at least two hours AFTER eating, take dose, and wait one hour before eating 
anything again. We will tell you what day to start taking your study medicine.  We will call that 
Day 1.  Day 1 will be about 15-16 days before your scheduled bladder surgery.  On Day 1, you 
will take 4 tablets of study medicine (4 tablets = 1 dose of study medicine). 
 
• If your tablets contain erlotinib, each tablet will have 150 mg of erlotinib (150 mg per 
tablet x 4 tablets = 600 mg total dose of erlotinib).   
 
• If your tablets contain placebo, each tablet will have 0 mg of erlotinib and your total dose 
will be 0. 
 
In addition to the study tablets you may be instructed to apply to any uncomfortable skin 
reactions (if they were to occur – please see risk section below) clindamycin gel twice a day to 
lessen any redness or discomfort; if this does not improve the skin reactions you may be 
instructed to also apply to the affected skin reactions hydrocortisone cream twice daily two hours 
after applying the clindamycin gel. 
 
Please do not use these topical medications unless the study doctor specifically instructs you to 
use them.  
 
One week later, on Day 8, you will take your second dose (4 tablets) of study medicine. 
 
One week after that, on the day before your surgery, you will take your 3rd (last) dose (4 tablets) 
of study medicine.  We call a few days before your surgery and tell you what time to take this 
last dose.   
 
(Note: if your surgery or cystoscopy with biopsy is delayed for any reason, you may be asked to 
take one additional weekly dose of study medicine.  4 total doses of study agent are the most that 
you can take on this study).  
 
During the study: 
 
Phone Contact (approximately 24-72 Hours Prior to Day 8 Visit): 
One to three days before your Day 8 Visit, we will call you to remind you of your appointment 
time/date.  We will also give you instructions on when to take your weekly dose of study 
medicine.   
 
On Day 8* (7 days after your first dose of study medicine) you will be asked to return to the 
clinic for another study visit.  Bring your study calendar along with you to this visit. 
 
At this visit we will do the following tests or procedures which are not part of the usual treatment 
for a bladder tumor: 


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• Physical Exam and Vital Signs: The study doctor or nurse will do a brief physical 
exam and measure your temperature, pulse, blood pressure, and weight.  They 
will also ask you about any changes in your non-study medications and any 
symptoms, side effects or health problems you have noticed since you started the 
study. 
• Review your Study Calendar: Study staff will review your calendar to be sure you 
are taking the study medicine correctly.  
• Blood Tests: The same blood tests that were done at the screening baseline visit 
will be repeated at this visit.  
• Once these blood tests have been drawn, you can take your weekly dose of study 
medicine and in an hour you can eat. 
 
* The Day 8 visit is optional.  If you decide to not come to clinic on Day 8 we will call you at 
a number you provide to us and check how you are doing.  During this call we will discuss 
with you how you are feeling, if you are taking your study drug as instructed, and if you are 
taking any other drugs or supplements. 
 
Pre-surgery Phone Call: 
 
24 to 72 hours before the day that your bladder surgery is scheduled, we will call you to schedule 
your final study visit which will be on the day of your bladder surgery before you have your 
procedure.  We will also give you instructions on when to take your last weekly dose of study 
medicine.  This dose needs to be taken about 9-18 hours before your surgery or biopsy.  
Depending on what time your surgery or biopsy is scheduled to start, you may need to take this 
last dose at a different time than your other doses.   
 
Day of Surgery Visit:  
 
Your last study visit will be on the day of your surgery before you have the surgery.  At this visit, 
we will do the following: 
 
• Physical Exam and Vital Signs 
• The study doctor or nurse will do a brief physical exam and measure your 
temperature, pulse, blood pressure, and weight.  They will also ask you about any 
changes in your non-study medications and any symptoms, side effects or health 
problems you have noticed since you started the study. 
• The study staff will ask you to fill out a survey about your urinary symptoms 
• Review your Study Calendar: Study staff will review your calendar to be sure you 
took the study medicine correctly. 
• Blood Tests: The same blood tests that were done at the screening baseline visit 
will be repeated at this visit.  
• After your surgery, the tissue that is taken from your bladder is sent to the 
pathology lab at your clinic or hospital.  After the pathology looks at the bladder 
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for a piece of the left over tissue.  We will use this tissue to run some tests to tell 
us more about the effects of the study medicine on the bladder tissue. 
 
Post-surgery Phone Call: 
 
 
Seven to fourteen days after your surgery or biopsy, we will call you by phone to ask you about 
any symptoms, side effects or health problems you have noticed since you started the study.   
 
Note: While you are participating in this study, we will watch you carefully for any side effects 
from the study medicine.  If you develop side effects we may cut your weekly dose of study 
medicine in half (to 2 tablets each week) or we may ask you to stop taking the study medicine.  If 
you stop taking the study medicine we would still like to have you come in for your surgery visit 
if you are willing. 
 
What risks can I expect from taking part in this study?  
 
If you choose to take part in this study, there is a risk that you may:  
 
• Lose time at work or home and spend more time in the hospital or doctor’s office than 
usual. 
• Be asked sensitive or private questions which you normally do not discuss. 
• Have a slight discomfort from the needle stick when blood is drawn or bruising at the site 
of the needle stick.  In rare instances some people faint during a blood draw or develop an 
infection at the site of the needle stick. 
 
Reproductive Risks:  You should not get pregnant, breastfeed, or father a baby while in this 
study.  The erlotinib used in this study could be very damaging to an unborn baby.  Check with 
the study doctor about what types of birth control, or pregnancy prevention, to use while in this 
study. 
 
The medicine used in this study may affect how different parts of your body work, such as your 
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health.  
 
There is also a risk that you could have side effects.  
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away.  
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death.  
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 


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• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• Tell the study doctor if you experience any unexplained, persistent cough. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common side effects that we know about erlotinib, some of 
which may be serious. There might be other side effects that we do not yet know about. If 
important new side effects are found, the study doctor will discuss these with you. 
 
 
Possible Side Effects of Erlotinib 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving erlotinib, more than 20 may have: 
• Rash  
• 
Diarrhea  
• 
Loss of appetite 
• 
Tiredness or fatigue 
• 
Shortness of breath 
• 
Cough 
• 
Nausea 
• 
Infection 
• 
Vomiting 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving erlotinib, from 4 to 20 may have: 
• Sores in the mouth 
• 
Itching 
• Acne 
• Dry skin 
• Weight loss 
• Irritation (redness, swelling, warmth, and pain) or infection of the skin around 
fingernails or toenails 
• Eye infection/pink eye 
• Dry eyes 
• 
Stomach pain or pain in the abdomen (belly) 
• 
Red bumps on the skin that are red, sore, and possibly infected  
 
 
 


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POSSIBLE, SOME MAY BE SERIOUS 
The frequency of some individual side effects for people receiving erlotinib has not yet been 
determined: 
• Shoulder pain 
• Change in urine color 
• Indigestion 
• Gas in the belly, burping 
• Irritability (easily annoyed or made angry) 
• Swelling of the face, hands, feet or ankles 
• Runny nose 
• Dizziness 
• 
Headache 
• 
Blood clot in the lung which may cause pain, shortness of breath 
• 
Stroke (Stoppage of blood flow to your brain which may cause paralysis, weakness, 
headache) 
• 
Death or injury to unborn baby 
• 
Because of the potential harm to the infant, women should be advised against breast-
feeding while receiving erlotinib therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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RARE, SOME MAY BE SERIOUS 
In 100 people receiving erlotinib, 3 or fewer may have: 
     Although very rare, some of the side effects listed below can cause death 
• Abnormal laboratory result which may indicate liver damage 
• Liver damage 
• Kidney damage which may cause swelling, may require dialysis 
• Swelling, irritation, or scarring of the lungs, which may cause pain or difficulty 
breathing.  
• A tear or hole in the stomach that may require surgery. More common in people with 
ulcers (sores in the stomach), diverticulitis (redness, pain, and swelling of part of the 
belly), and in people who take some types of drugs (NSAIDS, corticosteroids, 
chemotherapy). Talk to your study doctor about drugs to avoid.  
• Severe blistering or peeling of the skin 
• Patches of skin may become darker in color 
• Redness, swelling, sores, or a tear or hole in eye which may cause pain or blurred 
vision. 
• Increased bleeding (internal bleeding, nose bleed). More common in people who take 
blood thinning drugs.  
• Increased body hair growth, hair loss, eyelash/eyebrow changes, or brittle/loose 
fingernails or toenails. 
• Severe diarrhea or vomiting can cause an imbalance of minerals in the blood (called 
electrolytes) such as low potassium, with symptoms that may include weakness, 
fatigue, muscle cramps, or constipation. 
• 
In people with cancer of the pancreas who took combined treatment of erlotinib plus 
gemcitabine: heart attack, stroke, decreased red blood cells (anemia) which may cause 
tiredness, or may require blood transfusion, and decreased platelets which may cause easy 
bleeding, or longer bleeding. 
 
 
 


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Will I benefit from this study? 
 
Participating in this study is unlikely to help your condition. This study may help us learn things that 
could help people in the future. 
 
Can I stop taking part in this study? 
 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the 
study doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not 
to let the study doctor continue to provide your medical information to the organization running the study. 
 
We will tell you about any new information or changes in the study that could affect your health 
or your willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• If your health changes.  
• If the study is no longer in your best interest. 
• If new information becomes available. 
• If you do not follow the study rules. 
• If the study is stopped early for any reason. 
 
What are my rights in this study? 
 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
 
For questions about your rights while in this study, Insert your IRB’s contact information or 
your IRB’s designated Patient Relations/Rights Representative’s contact information. 
 
What are the costs of taking part in this study? 
 
The study medicine will be supplied at no charge while you take part in this study. The cost of 
study-specific exams, tests, and procedures will be paid for by the study. 
 
Some costs associated with your care may be considered standard of care, and will be billed to 
you or your insurance company. You will have to pay for any costs (including deductibles and 
co-payments) not covered by your health insurer. 
 
Before you decide to be in the study, you should check with your health plan or insurance 
company to find out exactly what they will pay for.  
 
You will receive $XX.XX to cover the cost of travel and other expenses associated with the study 
baseline/screening visit.  If you are found to be eligible and decide to participate in this study, 
you will receive an additional $XX.XX to cover the costs of travel and expenses associated with 


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participation in this study.  (This section may vary depending on how you elect to set up your 
participant reimbursements) 
 
What happens if I am injured or hurt because I took part in this study? 
 
In the event that you are physically injured as a result of participating in this research, emergency 
care will be available. You will, however, be responsible for the charges for emergency care. 
There is no commitment to provide any compensation for research-related injury. You should 
realize, however, that you have not released this institution from liability for negligence. Please 
contact your study doctor or the study investigator, Insert PI Name at Insert PI phone number if 
you are injured or for further information. 
 
It is important that you tell your study doctor or the study investigator, Insert PI Name, if you 
feel that you have been injured because of taking part in this study. You can tell the doctor in 
person or call him/her at Insert PI phone number if you are injured or wish further information. 
 
Who will see my medical information?  
 
Your privacy is very important to us and we will make every effort to protect it. Your 
information may be given out if required by law. For example, certain states require doctors to 
report to health boards if they find a disease like tuberculosis. However, we will do our best to 
make sure that any information that is released will not be able to identify you. There are 
organizations that may inspect your records. These organizations are required to make sure your 
information is kept private. Some of these organizations are: 
• 
The Institutional Review Board, IRB, is a group of people who review the research 
with the goal of protecting the people who take part in the study. 
• 
The Food and Drug Administration and the National Cancer Institute in the US, and 
similar organizations if other countries are involved in the study. 
• 
The National Cancer Institute will obtain information for this clinical trial under data 
collection authority Title 42 U.S.C. 285. 
• 
The study sponsor and Astellas Pharma Global Development, Inc. (formerly OSI 
Pharmaceuticals, Inc.), the drug company providing the study drug for this study. 
If information from this study is published or presented at scientific meetings, your name and 
other personal information will not be used.   
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 
• Personnel from the University of Wisconsin Comprehensive Cancer Center in 
charge of quality assurance. 
• Contractors hired by the government to review study files. 
• Data will be stored on computer files at the University of Wisconsin and the 
National Cancer Institute’s statistical center. 
 
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research. If you do, we will inform them of your participation. 
 
 
Special Concerns 
 
Erlotinib can interact with some kinds of antibiotics, antiviral, and antifungal drugs, and warfarin 
(a blood thinner).  You should make sure you have told your cancer doctor about all medicines 
you are using, and make sure your local doctor knows you are taking erlotinib if they prescribe 
any new ones.  Also, please contact your doctor if you experience any unexplained, persistent 
cough. 
 
Where can I get more information? 
 
You may visit the NCI website at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237).  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web  
site at any time. 
 
Who can answer my questions about this study? 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor, Insert PI Name at Insert PI phone 
number.  
 
Optional Tissue Banking for Possible Future Studies 
 
 
Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of 
this research is done using samples from biopsies, blood, urine, or other fluids. Through these 
studies, researchers hope to find new ways to prevent, detect, treat, or cure health problems.  
Some of these studies may be about genes. Genes carry information about features that are found 
in you and in people who are related to you. Researchers are interested in the way that genes 
affect how your body responds to treatment. 
 
We ask your permission to store and use your samples and health information for medical 
research. The research that may be done is unknown at this time. Storing samples for future 
studies is called “biobanking”. The Biobank is run by the National Cancer Institute. 
 
What is involved?  
 
If you agree to take part, any of your tissue samples remaining after we complete this study will 
be stored in the Biobank, along with samples and information from other people who take part. 


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The samples will be kept until they are used up. 
 
1) Qualified researchers can submit a request to use the materials stored in the Biobank. A 
research committee at the National Cancer Institute will review each request. There will 
also be an ethics review to ensure that the request is necessary and proper. Researchers 
will not be given your name or any other information that could directly identify you.  
2) Neither you nor your study doctor will be notified if/when research is conducted using 
your samples and no information on the results of this research will be placed in your 
medical records. 
3) Some of your genetic and health information may be placed in central databases that may 
be public, along with information from many other people. Information that could 
directly identify you will not be included.  
 
What are the possible risks? 
 
1) There is a risk that someone could get access to the personal information in your medical 
records or other information we have stored about you.  
2) There is a risk that someone could trace the information in a central database back to you. 
Even without your name or other identifiers, your genetic information is unique to you. 
The researchers believe the chance that someone will identify you is very small, but the 
risk may change in the future as people come up with new ways of tracing information.  
3) There are laws against the misuse of genetic information, but they may not give full 
protection. New health information about inherited traits that might affect you or your 
blood relatives could be found during a study. The researchers believe the chance these 
things will happen is very small, but cannot promise that they will not occur. 
 
 
How will information about me be kept private?  
 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take:  
 
1) When your sample(s) is sent to the Biobank, no information identifying you (such as your 
name or social security number) will be sent. Samples will be identified by a unique 
study code only.  
2) The list that links the unique code to your name will be kept separate from your sample 
and health information. The Biobank is required to keep your identity confidential. 
3) Researchers to whom the Biobank sends your sample and information will not know who 
you are. They must also sign an agreement that they will not try to find out who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) If research results are published, your name and other personal information will not be 
used. 
 
What are the possible benefits?  
 
You will not benefit from taking part.  
 


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The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
Are there any costs or payments? 
 
There are no costs to you or your insurance. You will not be paid for taking part.  If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 
profits. 
 
What if I change my mind? 
 
If you decide you no longer want your samples to be used, you can call the study doctor, Insert 
Study P.I. name at Insert P.I. phone number who will let the researchers know. Then, any sample 
that remains in the bank will no longer be used. Samples or related information that have already 
been given to or used by researchers will not be returned. 
 
WHAT IF I HAVE MORE QUESTIONS?  
If you have questions about the use of your samples for research, contact the study doctor, Insert 
Study P.I. name at Insert P.I. phone number  
 
Please circle your answer to show whether or not you would like to take part in each option  
 
SAMPLES FOR FUTURE RESEARCH STUDIES: 
 
 
My samples and related information may be kept in a Biobank for use in future health 
research. 
 
 
 
YES 
 
NO 
 
 
I agree that my study doctor, or their representative, may contact me or my physician to 
see if I wish to participate in other research in the future. 
 
 
 
YES 
 
NO 
 
 
This is the end of the section about optional studies. 
 
 
 
 
 
 
 


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My Signature Agreeing to Take Part in the Main Study 
 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any tissue banking where I circled ‘yes’.  
 
________________________________ 
_______________________________ 
Participant’s signature 
 
 
 
Date of signature 
 
________________________________ 
_______________________________  
Signature of person(s) conducting the  
 
Date of signature  
informed consent discussion