Clinical trial NCT00749892
Conditions: Recurrent Bladder Urothelial Carcinoma Recurrent Renal Pelvis Urothelial Carcinoma Recurrent Ureter Urothelial Carcinoma Recurrent Urethral Urothelial Carcinoma Stage 0a Bladder Cancer AJCC v8 Stage 0a Renal Pelvis Cancer AJCC v8 Stage 0a Ureter Cancer AJCC v8 Stage 0a Urethral Cancer AJCC v8 Stage 0is Bladder Cancer AJCC v8 Stage 0is Renal Pelvis Cancer AJCC v8 Stage 0is Ureter Cancer AJCC v8 Stage 0is Urethral Cancer AJCC v8 Stage II Bladder Cancer AJCC v8 Stage II Renal Pelvis Cancer AJCC v8 Stage II Ureter Cancer AJCC v8 Stage II Urethral Cancer AJCC v8 Stage III Renal Pelvis Cancer AJCC v8 Stage III Ureter Cancer AJCC v8 Stage III Urethral Cancer AJCC v8 Stage IIIA Bladder Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center
Start date: 2008-06-10; Completion date: 2019-11-26
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well erlotinib hydrochloride works in Treating participants with muscle invasive urothelial cancer or urothelial cancer that has come back. Drugs used in chemotherapy, such as erlotinib hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the response rate (ie: pT0 rate) of patients with urothelial cancer treated with erlotinib prior to cystectomy.

SECONDARY OBJECTIVES:

I. To estimate the 4-year disease-free survival of patients with urothelial cancer treated with erlotinib prior to cystectomy.

II. To measure epithelial-mesenchymal transition (EMT) markers (E-cadherin, HER4, PDGFR-beta, vimentin, fibronectin) in pre- and post-treatment biopsies and correlate expression patterns with the biological responses measured below.

III. To quantify target inhibition, antiproliferation (KI-67), and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling \[TUNEL\]) in biopsies obtained from patients before, during, and after therapy.

IV. Interrogate membrane (phosphorylated EGFR) and downstream receptor signaling pathways (ERKs, AKT/mTOR, GSK-3beta) to provide further insight into whether or not a given tumor displays a biological response.

V. To correlate the changes in Ki-67 expression with changes in angiogenesis and angiogenesis related gene expression utilizing fluorescent tissue staining techniques that we have developed in the laboratory (such as two-color TUNEL, phosphor-receptor, and microvessel density.) VI. To profile messenger ribonucleic acid (mRNA) expression in pre- and post-treatment biopsies using Affymetrix arrays and correlate the changes observed with EMT, growth arrest, and apoptosis.

VII. To quantify EGFR copy number and correlate with changes observed with EMT, growth arrest, and apoptosis.

OUTLINE:

Participants receive erlotinib hydrochloride orally (PO) once daily (QD) for 3-5 weeks in the absence of disease progression or unacceptable toxicity. Within 24 hours of the last dose, participants undergo cystectomy.

After completion of study treatment, participants are followed up every 6 months for 1 year, then annually for 4 years.

Arms: arm 1: Participants receive erlotinib hydrochloride PO QD for 3-5 weeks in the absence of disease progression or unacceptable toxicity. Within 24 hours of the last dose, participants undergo cystectomy.
Interventions: intervention 1: Erlotinib Hydrochloride
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2007-0704 
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Page i 
This is a CONFIDENTIAL document provided by, Genentech, Inc. 
Version date:  01-May-2005 
 
Tarceva Investigator Sponsored Trial PROTOCOL TEMPLATE 
 
 
TITLE: 
A Phase II Exploratory Study of Pre-Operative 
Treatment with Erlotinib (Tarceva) in Muscle 
Invasive or Recurrent Transitional Cell 
Carcinoma Requiring Cystectomy 
PROTOCOL NUMBER: 
OSI4222 
STUDY DRUG: 
Tarceva™ (erlotinib; OSI-774) 
 
 
PRINCIPAL INVESTIGATOR
 
Arlene Siefker-Radtke, M. D.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ii 
 
TABLE OF CONTENTS 
 
SYNOPSIS..............................................................ERROR! BOOKMARK NOT DEFINED. 
1. 
BACKGROUND ............................................................................................................. 1 
1.1 
EPIDERMAL GROWTH FACTOR RECEPTOR EXPRESSION AND SIGNIFICANCE IN 
CANCER ................................................................................................................................. 2 
1.2 
TARCEVA AS AN EGFR TYROSINE KINASE INHIBITOR.............................................. 3 
1.2.1 
Non-clinical Data.............................................................................................. 3 
1.2.2 
Clinical Experience with Tarceva..................................................................... 4 
1.3 
STUDY RATIONALE.................................................................................................... 7 
2. 
OBJECTIVES ................................................................................................................. 7 
2.1 
PRIMARY OBJECTIVE ................................................................................................. 7 
2.2 
SECONDARY OBJECTIVE(S)........................................................................................ 8 
3. 
STUDY DESIGN............................................................................................................. 8 
3.1 
DESCRIPTION OF THE STUDY...................................................................................... 8 
3.2 
RATIONALE FOR STUDY DESIGN.............................................................................. 10 
3.3 
SAFETY PLAN........................................................................................................... 11 
3.3.2 
General Plan to Manage Safety Concerns...................................................... 13 
3.4 
ADMINISTRATIVE STRUCTURE ................................................................................. 14 
3.5 
COMPLIANCE WITH LAWS AND REGULATIONS......................................................... 15 
4. 
MATERIALS AND METHODS ................................................................................. 16 
4.1 
PATIENTS................................................................................................................. 16 
4.1.1 
INCLUSION CRITERIA.................................................................................. 16 
Patients must fulfill all of the following criteria to be eligible for study entry: ............. 16 
4.1.2 
EXCLUSION CRITERIA................................................................................. 18 
4.2 
METHOD OF TREATMENT ASSIGNMENT................................................................... 18 
4.3 
STUDY TREATMENT................................................................................................. 18 
4.3.1 
Formulation .................................................................................................... 18 
4.3.2 
Dosage, Administration, and Storage............................................................. 19 
4.3.3 
Dose Modification........................................................................................... 19 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES............................................................. 21 
4.5 
STUDY ASSESSMENTS (SEE APPENDIX 1).................................................................. 22 


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4.5.1 
SCREENING AND PRETREATMENT ASSESSMENTS................................. 23 
4.5.2 
EVALUATIONS AND PROCEDURES DURING TREATMENT ................... 24 
4.5.3 
TREATMENT DISCONTINUATION ASSESSMENTS ................................... 24 
4.5.4 
FOLLOW-UP ASSESSMENTS ....................................................................... 24 
4.6 
ASSAY METHODS..................................................................................................... 24 
4.7 
PATIENT DISCONTINUATION .................................................................................... 25 
4.8 
STATISTICAL METHODS ........................................................................................... 26 
Determination of Sample and Monitoring for Efficacy .................................................. 26 
4.8.1 
Analysis of the Conduct of the Study............................................................... 28 
4.8.2 
Analysis of Demographic and Baseline Characteristics ................................ 28 
4.8.3 
Efficacy Analysis............................................................................................. 28 
4.8.4 
Safety Analysis ................................................................................................ 28 
4.8.5 
Pharmacokinetic (?) Analyses ........................................................................ 29 
4.8.6 
Missing Data................................................................................................... 29 
4.9 
DATA QUALITY ASSURANCE ................................................................................... 29 
5. 
ASSESSMENT OF SAFETY....................................................................................... 30 
5.1 
SPECIFICATION OF SAFETY VARIABLES ................................................................... 30 
5.1.1 
Adverse Events................................................................................................ 30 
5.1.2 
Serious Adverse Events................................................................................... 31 
5.2 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES...... 31 
5.2.1 
Adverse Event Reporting Period..................................................................... 32 
5.2.2 
Assessment of Adverse Events......................................................................... 32 
5.2.3 
SAE Reporting Guidelines .............................................................................. 34 
5.3 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS...... 34 
5.3.1 
Eliciting Adverse Events ................................................................................. 34 
5.4 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS............... 35 
5.5 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS......... 35 
6 
SPONSOR AND INVESTIGATOR REQUIREMENTS.......................................... 36 
6.1 
STUDY INITIATION ................................................................................................... 36 
6.2 
STUDY COMPLETION................................................................................................ 36 
6.3 
INFORMED CONSENT................................................................................................ 37 
6.4 
INSTITUTIONAL REVIEW BOARD APPROVAL............................................................ 37 
6.5 
STUDY MONITORING REQUIREMENTS...................................................................... 37 
6.6 
DATA COLLECTION.................................................................................................. 38 


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6.7 
STUDY MEDICATION ACCOUNTABILITY................................................................... 38 
6.8 
DISCLOSURE OF DATA ............................................................................................. 39 
6.9 
RETENTION OF RECORDS ......................................................................................... 39 
7. 
REFERENCES.............................................................................................................. 40 
APPENDIX A........................................................................................................................ 43 
APPENDIX B ........................................................................................................................ 44 
APPENDIX C........................................................................................................................ 44 
 


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1. 
BACKGROUND 
There is growing evidence supporting neoadjuvant therapy for transitional cell 
carcinomas confined to the bladder.1 However, for the appropriately selected 
group of patients with tumor invading the muscle wall (i.e. clinical T2 tumors), 
the evidence is not so clear.  Though many patients may be cured by surgical 
resection alone, there is a subset of these patients who relapse and develop 
incurable metastatic disease.  Therefore, while one may not want to put these 
patients through the toxicity of systemic multi-agent chemotherapy, there is 
certainly the feeling that something further must be done.  Since, at the 
current time, these patients often undergo radical cystectomy where the entire 
bladder, prostate and regional lymph nodes are removed, this group of 
untreated patients with intact bladders provides an ideal opportunity to 
explore new agents and collect tissue specimens to measure candidate 
prospective markers of response, receptor phosphorylation, and other 
downstream targets of biological agents.   
Among the numerous biological targets implicated in transitional cell 
carcinoma progression, inhibitors of the epidermal growth factor receptor 
(EGF-R) remain extremely attractive.  The receptor for EGF-R is over-
expressed by more than 75% of all human TCC, with the level of expression 
correlating directly with tumor grade, stage, and survival.2 Numerous studies 
have demonstrated that clinically relevant inhibitors of the EGF-R, strongly 
inhibit the growth of human bladder tumor xenografts.3,4 Thus, there is 
compelling rationale to target these pathways in this patient population. 
However, EGFR inhibitors have not displayed consistent activity in clinical 
trials performed in other disease sites, which has dampened clinical 
enthusiasm for aggressively developing them further.  Studies performed 
within the context of non-small cell lung cancer demonstrated that clinical 
responses were linked to activating mutations within the EGFR tyrosine 
kinase domain, suggesting that a better understanding of the biological 
effects of EGFR inhibitors on tumor cells will help to identify tumors that will 
respond (biologically or clinically) to therapy.   
Although none of the urothelial carcinoma cell lines nor any of 75 primary 
tumors we evaluated contained activating EGFR kinase domain mutations or 
expressed the truncated form of the EGFR (EGFRvIII) that mediates ligand-
independent signaling and promotes tumor growth in other model systems, 
we found that EGFR inhibitors (gefitinib or cetuximab) blocked cell cycle 
progression in 8/20 human bladder cancer cell lines.  Through a large 
collaborative effort in our Bladder SPORE program, with a Core Project 
studying EGF-R inhibition in urothelial cancer, we have identified molecular 
mechanisms that appear to correlate with or mediate these effects.   
Consistent with emerging evidence from other solid tumors, is the so-called 
“epithelial to mesenchymal transition” (EMT) which correlates with resistance 


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to EGFR antagonist-induced growth inhibition.  Specifically, the sensitivity to 
EGFR inhibition in urothelial carcinoma as defined by cell cycle arrest was 
proportional to the pre-treatment expression of E-cadherin and HER4, and 
inversely proportional to the expression of PDGFR-β, a mesenchymal growth 
factor receptor. Moreover, the response to therapy could be predicted ‘early’ 
in the course of treatment by quantifying changes in the expression of 
proliferation markers, including Ki-67/PCNA, p27, Cyclin D1, and GSK-3-β. 
Thus, we have designed a proof-of-principle clinical trial to provide 
information to prospectively identify tumors likely to respond to this form of 
therapy.  Knowledge gained from this trial may have substantial impact in 
bladder cancer, including the setting of secondary chemoprevention, or in 
future combinations with other agents. 
 
1.1 
EPIDERMAL GROWTH FACTOR RECEPTOR EXPRESSION AND 
SIGNIFICANCE IN CANCER  
The control of cell growth is mediated by a complex network of signaling 
pathways responsive to external influences, such as growth factors, as well 
as to internal controls and checks.  Epidermal growth factor (EGF) was one of 
the first growth factors to be described.  It was shown to be mitogenic, an 
effect mediated by the binding of EGF (or other ligands) to the cell surface 
EGF receptor (EGFR), stimulating autophosphorylation of the intracellular 
tyrosine kinase domain of the receptor.  Subsequent investigations revealed 
EGFR to be one of a family of closely related receptors that includes EGFR 
(HER1), HER2, HER3, and HER4.   
EGFR and other HER family members are considered to be important in the 
development, progression, and aggressive behavior of human epithelial 
malignancies and to be relevant therapeutic targets.  A number of human 
malignancies are associated with aberrant or over-expression of EGFR 
(Salomon et al. 1995).  Stimulation of tumor cells via the EGFR is important 
for both tumor growth and tumor survival in vivo.  Over-expression of EGFR in 
certain human tumors, including non–small cell lung carcinoma (NSCLC), has 
been correlated with both chemo-resistance and poor prognosis (Rusch et al. 
1996, 1997; Davies and Chamberlin 1996; Veale et al. 1987, 1993; Sekine 
et al. 1998; Pfeiffer et al. 1996; Cerny et al. 1986; IMPATH Inc 1998–1999; 
Reissmann et al. 1999; Fujino 1996; Fontanini et al. 1995; Lei et al. 1999). 
Inhibitors of EGFR tyrosine kinase activity have been in development for a 
number of years, and although earlier compounds lacked specificity and 
potency, newer compounds have proven active in nonclinical and clinical 
studies. 
Tarceva (previously known as OSI-774) is an orally active, potent, selective 
inhibitor of the EGFR tyrosine kinase.  Early clinical data with Tarceva 


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indicate that the compound is generally safe and well tolerated at doses that 
provide the targeted effective concentration based on nonclinical 
experiments.  A recently completed, randomized, double-blind, placebo-
controlled trial has shown that Tarceva as a single agent significantly 
improves the survival of patients with incurable Stage IIIb/IV NSCLC who 
have failed standard therapy for advanced or metastatic disease (Shepherd et 
al; Proceedings of ASCO 2004; Abst 7022). 
1.2 
TARCEVA AS AN EGFR TYROSINE KINASE INHIBITOR 
Tarceva is an EGFR tyrosine kinase inhibitor that has been investigated in 
several Phase III studies.  An overview of relevant nonclinical and clinical 
information is presented below; complete details are available in the 
Tarceva™ Investigator Brochure. 
1.2.1 Non-clinical Data 
a. Pharmacology 
Tarceva, a quinazoline, directly and reversibly inhibits the human EGFR 
tyrosine kinase with an IC50 of 2 nM (0.79 ng/mL) in an in vitro enzyme assay 
and reduces EGFR autophosphorylation in intact tumor cells with an IC50 of 
20 nM (7.9 ng/mL).  This potent inhibition is selective for the EGFR tyrosine 
kinase both in assays assessing the effects of Tarceva on a variety of other 
isolated tyrosine kinases and in cellular bioassays designed to isolate this 
functional pathway.  Tarceva is designed to inhibit EGF-dependent 
proliferation of cells at submicromolar concentrations and blocks cell cycle 
progression in the G1 phase.  
Data on drug exposure and anti-tumor responses in human tumor xenograft 
models (HN5 and A431) were analyzed in order to estimate the plasma 
concentration of erlotinib associated with anti-tumor activity.  Based on these 
efficacy models, the minimum steady-state plasma concentration targeted for 
clinical activity in humans is projected to be 500 ng/mL. 
b. Toxicology 
Toxicology studies have been performed in mice, rats (up to 6 months), dogs 
(up to 1 year), and monkeys (1 week).  Treatment-related effects observed in 
at least one species or study included effects on the cornea (atrophy, 
ulceration), skin (follicular degeneration and inflammation, redness, and 
alopecia), ovary (atrophy), liver (necrosis), kidney (papillary necrosis and 
tubular dilatation), lacrimal glands (atrophy), salivary glands (atrophy), 
mandibular lymph nodes (inflammation), spleen (hematopoiesis), 
gastrointestinal tract (delayed gastric emptying and diarrhea), and embryo-
fetal toxicity.  Red blood cell parameters were decreased, and white blood 
cells (primarily neutrophils) were increased.  There were treatment-related 


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increases in ALT, AST, triglyceride and bilirubin and decreases in albumin; 
increases in bilirubin were likely caused by a treatment-related impairment of 
bilirubin metabolism.  
 
1.2.2 Clinical Experience with Tarceva 
a. Dose Selection for Single-Agent Trials of Tarceva 
Phase I trials of Tarceva explored both schedule and dose to evaluate the 
safety, tolerability, and pharmacokinetic profile of the compound given as a 
single agent.  A number of pharmacokinetic trials in healthy subjects have 
been conducted, along with three classic Phase I trials in patients with 
advanced cancer.  The single-agent maximum tolerated dose (MTD) was 
estimated to be 150 mg administered once daily.   
The primary toxicities of single-agent Tarceva consisted of rash (dermatosis), 
diarrhea, nausea, fatigue, stomatitis, vomiting, and headache.  When given 
daily, dose-limiting toxicity (diarrhea) was observed at 200 mg/day.  At 
150 mg/day, diarrhea was manageable with the addition of loperamide 
therapy; this dose was considered the maximal tolerated dose.  
Rash (variously referred to as dermatitis, acneiform rash, or maculopapular 
rash) has been variable in onset, duration, and severity, but typically appears 
on the face, neck, scalp, chest, and back starting after ~1 week of treatment.  
The mechanistic basis of the rash remains uncertain; histopathologic 
examination of biopsies of the rash demonstrated inflammatory cell infiltrate 
and mild epidermal hyperproliferation.  In some cases, the rash gradually 
improved despite continued dosing and, in general, resolved without sequelae 
following Tarceva discontinuation.  The rash did not result in study 
discontinuation in patients with cancer in the Phase I trials.  Laboratory 
abnormalities observed infrequently with single-agent Tarceva involved 
primarily liver function tests, including elevation of ALT, AST, and/or bilirubin. 
Selection of the 150 mg/day dose of Tarceva for subsequent single-agent 
studies was based on pharmacokinetic parameters, as well as the safety and 
tolerability profile of this dose in Phase I trials in heavily pretreated patients 
with advanced cancer.  Drug levels seen in patients with cancer receiving the 
150 mg/day dose were consistently above the average plasma concentration 
of 500 ng/mL targeted for clinical efficacy.  
b. Pharmacokinetics 
Oral Tarceva is well absorbed and has an extended absorption phase, with 
mean peak plasma levels occurring at 3 hours after oral dosing of 150 mg/dL 
at steady state.  A study in healthy subjects provided an estimate of 
bioavailability of 59% (95% CI:  55%, 63%).  The time to reach steady-state 
plasma concentration was ~5 days.  The accumulation ratio with daily dosing 


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of Tarceva was estimated to be 2.0.  From a population pharmacokinetic 
analysis of 708 patients, the median trough concentration (Cmin) 24 hours 
following the previous dose was 1041 (±697) ng/mL.  Median AUC achieved 
during the dosing interval at steady state was 19,801 ng • hr/mL.  Exposure 
after an oral dose is increased by food.   
There is extensive binding of Tarceva and metabolites to both serum albumin 
and AAG (alpha-1-acid glycoprotein), with total plasma protein binding for 
Tarceva and OSI-420 of ~95% and 91%, respectively.  Tarceva is extensively 
metabolized in the liver by the hepatic cytochromes in humans–primarily by 
CYP3A4 and to a lesser extent by CYP1A2.  The primary metabolite of 
Tarceva, OSI-420, has potency comparable to that of erlotinib, but is present 
at levels that are < 10% of erlotinib levels.  Tarceva is excreted predominantly 
via the feces (> 90%).  The elimination half-life after a 150-mg oral dose is 
~30 hours.  In population-based data analyses, no relationships were 
identified between predicted steady-state trough concentration and patient 
age, body weight, sex, ethnicity, or creatinine clearance. 
c. Phase II and III Trials in Patients with Advanced Cancer  
Multiple Phase II trials evaluating the safety, tolerability, and antitumor activity 
of Tarceva have been conducted in patients with advanced, refractory 
malignancies including cancer of the head and neck, lung, aerodigestive tract, 
ovary, breast, central nervous system (glioma), and others. Tarceva has been 
evaluated both as a single agent and administered concurrently with 
conventional chemotherapy agents using various doses and schedules.     
Evidence of activity has been observed in squamous cell carcinoma of the 
head and neck, ovarian, breast and pancreatic carcinoma, non–small cell 
lung cancer (NSCLC), and glioblastoma multiforme (GBM).  Patients received 
150 mg/day of Tarceva in all of these studies except the GBM study where 
dose escalation was allowed until limited by rash and where a higher starting 
dose was tested in subjects receiving concomitant enzyme inducing anti-
epileptic drugs.  Dose reduction was allowed in all studies in the case of 
intolerance.  Diarrhea was treated with loperamide therapy and/or dose 
reduction.  Rash was treated with a variety of agents, including oral and 
topical antibiotics, corticosteroids, and other agents.   
Patients receiving Tarceva in combination with various chemotherapy agents 
have generally experienced the same type of adverse events (AEs) as with 
either agent alone.   
The first randomized placebo controlled trial to demonstrate a survival 
advantage for an EGFR inhibitor was the Phase III study, BR21.  This 
international trial, conducted by the National Cancer Institute of Canada 
Clinical Trial Group (NCIC CTG), included 731 patients with incurable Stage 


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IIIb/IV NSCLC who have failed standard therapy for advanced or metastatic 
disease.  Patients randomized in a 2:1 ratio to single-agent Tarceva 150 
mg/day obtained a 42.5% improvement in median survival over placebo, from 
4.7 to 6.7 months.  The one-year survival increased significantly (from 22% to 
31%) as did the median and 6 month PFS, response rate, and the time to 
deterioration of tumor related symptoms of pain, cough, and dyspnea.  
(Shepherd 2004). 
In BR-21, of the 727 patients evaluable for safety (485 Tarceva, 242 placebo), 
the most common AEs in the Tarceva arm were rash (75% Tarceva, 17% 
placebo), diarrhea (54% Tarceva, 18% placebo) and stomatitis (17% Tarceva, 
18% placebo) events.  The majority of these events were mild to moderate in 
severity.  The incidence of ILD reported was the same in the placebo and 
Tarceva groups at 0.8% in each arm. 
Two large, Phase III, randomized studies in first-line NSCLC patients 
evaluated Tarceva in combination with platinum-based two-drug combination 
chemotherapy.  A total of 1079 previously untreated patients received 
carboplatin/paclitaxel with either Tarceva or placebo in the TRIBUTE trial 
(OSI2298g) conducted in the United States.  An additional 1172 patients 
received cisplatin/gemcitabine plus either Tarceva or placebo in the TALENT 
trial (BO16411) conducted in 27 countries in Europe and other ex-U.S. 
locations.  Neither study met its primary endpoint of improved overall survival 
or a secondary endpoint of improved time to disease progression or overall 
response rate.  Overall, the number of adverse events and serious adverse 
events were well balanced between the two arms of each study, with two 
exceptions.  As expected, rash and diarrhea occurred more frequently in the 
Tarceva arms.  In the TRIBUTE study, more serious adverse events resulting 
in death were seen in the Tarceva arm compared with the placebo arm (53 
vs. 27).  Most of the apparent imbalance was due to events reported as 
pneumonia or progression of underlying cancer. (Gatzemeier U. et al.- Talent 
trial  - ASCO 2004 - Abstract 7010 and Herbst R. et al. – Tribute trial - ASCO 
2004 - Abstract 7011). 
d. Patients with Hepatic or Renal impairment 
The influence of hepatic metastases and/or hepatic dysfunction on the 
pharmacokinetics of Tarceva is not yet known.  However, Tarceva is cleared 
predominately by the liver, and caution should be used when administering 
Tarceva to patients with hepatic dysfunction. Tarceva is also a strong inhibitor 
of the UDP-glucuronosyltransferase UGT1A1 enzyme responsible for the 
glucuronidation of bilirubin.  Hyperbilirubinemia appears most often to be a 
side effect related to genetic polymorphisms of UGT1A1.  Rare cases of 
hepatic failure (including fatalities) have been reported during the 
postmarketing use of Tarceva.  Confounding factors for severe hepatic 


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dysfunction have included pre-existing liver disease such as cirrhosis, viral 
hepatitis, hepatocellular carcinoma, hepatic metastases, or concomitant 
treatment with potentially hepatotoxic drugs. 
Rare cases of myocardial infarction (including fatalities) have been reported 
during the postmarketing use of Tarceva. 
No clinical studies have been conducted in patients with compromised renal 
function since Tarceva and its metabolites are not significantly excreted by 
the kidneys.   
 
1.3 
STUDY RATIONALE 
The receptor for EGF-R is over-expressed in more than 75% of all human 
transitional cell tumors, with the level of expression correlating directly with 
tumor grade, stage, and survival.  In our pre-clinical models, clinically relevant 
inhibitors of the EGF-R strongly inhibit the growth of tumor cells in xenograft 
models.  While EGF-R mutational status has been predictive of response 
within the context of non-small cell lung cancer, we have not found these 
mutations to present in our cell lines nor in 75 primary tumors that were 
evaluated for activating EGFR kinase domain mutations or the truncated form 
of the EGF-R (EGFRvIII).  Despite these findings, we have observed  that 
EGFR inhibitors blocked cell cycle progression in 8/20 human bladder cancer  
cell lines.  Through a large collaborative effort in our Bladder SPORE program 
we have identified molecular mechanisms that appear to correlate with or 
mediate these effects. 
While the primary endpoint will be focused on clinical response, it is clear that 
that a strong inducement for this study is the proposed biologic endpoints.  
With our current model, we have the opportunity to study novel agents in the 
preoperative setting with the ability to collect tissue both prior to therapy (with 
tissue collected on routine cystoscopy), and at cystectomy.  Ultimately, we 
hope to use the knowledge gained from this descriptive study to identify 
appropriate patients for EGFR-directed or other selectively targeted therapies. 
 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE  
To estimate the response rate (ie: pT0 rate) of patients with urothelial cancer 
treated with erlotinib prior to cystectomy.  In this context, response will be 
defined as the absence of residual cancer in the resected specimen.  


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2.2 
SECONDARY OBJECTIVE(S) 
Clinical Objectives: 
1.  To estimate the 4-year disease-free survival of patients with urothelial 
cancer treated with erlotinib prior to cystectomy. 
Biologic Objectives: 
1.  To measure EMT markers (E-cadherin, HER4, PDGFR-beta, vimentin, 
fibronectin) in pre- and post-treatment biopsies and correlate expression 
patterns with the biological responses measured below. 
2. To quantify target inhibition, antiproliferation (KI-67), and apoptosis 
(TUNEL) in biopsies obtained from patients before, during, and after 
therapy. 
3. Interrogate membrane (phosphorylated EGFR) and downstream receptor 
signaling pathways (ERKs, AKT/mTOR, GSK-3beta) to provide further 
insight into whether or not a given tumor displays a biological response. 
4. To correlate the changes in Ki-67 expression with changes in angiogenesis 
and angiogenesis related gene expression utilizing fluorescent tissue 
staining techniques that we have developed in the laboratory (such as 
two-color TUNEL, phosphor-receptor, and microvessel density.) 
5. To profile mRNA expression in pre- and post-treatment biopsies using 
Affymetrix arrays and correlate the changes observed with EMT, growth 
arrest, and apoptosis. 
6.  To quantify EGFR copy number and correlate with changes observed with 
EMT, growth arrest, and apoptosis. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
Population: 
Patients must have invasive transitional cell carcinoma, and be candidates for 
cystectomy.  Patients with transitional cell tumors of the upper tract and urethra 
tumors may also be eligible. Patients with high-risk features including micropapillary 
features, small cell carcinoma, 3-D mass on EUA, and lymphovascular invasion, 
require treatment with systemic chemotherapy (figure 1) and therefore will be 
generally excluded from this study unless they refuse the recommended 
cytoreductive chemotherapy.   Patients may have received prior intravesical 
treatment for their tumor.  Patients treated with prior systemic chemotherapy for 


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urothelial carcinoma are not eligible for this study.  Patients with metastatic or 
surgically unresectable disease are not eligible for this study. 
Patient must have no significant co-morbidities interfering with treatment.  Patients 
with interstitial lung disease are not eligible for this trial. 
Since tumor response and target inhibition on patient tissue are end-points of the 
study, patients should agree to have biopsy and cystectomy at M. D. Anderson.  
Tissue collection is an optional procedure. 
 
Study Schema: 
This is a phase II exploratory study of pre-operative treatment with erlotinib for 
patients with muscle invasive transitional cell carcinoma.  The primary endpoint is 
pathologic response rate, with additional endpoints regarding target inhibition on 
patient tissue.  Biopsies will be obtained prior to therapy, and residual tumor will be 
collected at cystectomy. 
Treatment Regimen: 
Patients will receive erlotinib 150 mg po daily.  Patients will receive at least 3 weeks 
of therapy, scheduled so that the last dose of therapy will be given within 24 hours 
prior to cystectomy.   Since cystectomy will usually be scheduled within 3-5 weeks, 
therapy will not delay surgery.  The treatment may be shortened, if necessary, to 
accommodate the surgical schedule, but will generally last for 3 weeks.  
Figure 1: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Organ Confined  
Urothelial Cancer 
Muscle Invasive (cT2) 
High risk features: 
¥ Micropapillary
¥ Small cell 
¥ Lymphovascular invasion
¥ 3-D mass on EUA (cT3b)
Cytotoxic Chemotherapy 
Erlotinib 
Daily  x 3 weeks 
Preoperative Study   of  Pharmacodynamic 
Markers Following Erlotinib 


Protocol 2007-0704 
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3.2 
RATIONALE FOR STUDY DESIGN 
 
Current Clinical Practice: 
Our current clinical practice for low-risk muscle invasive bladder cancer, is to 
proceed with cystectomy, and consider additional adjuvant chemotherapy 
depending upon pathologic stage.  Though many of these patients may be 
cured by surgical resection alone, there is a subset of these patients who 
relapse and develop incurable metastatic disease.  Neoadjuvant 
cytoreductive chemotherapy is given only for those patients with the following 
high-risk features: micropapillary tumor, small cell tumor, 3-D mass on EUA, 
and lymphovascular invasion.   
Clinical Endpoint Rationale: 
 (Please also see section 1.3 for rationale regarding exploring EGFR targeted 
therapy in bladder cancer). 
 
Though many patients may be cured by surgical resection alone, there is a 
subset of these patients who relapse and develop incurable metastatic 
disease.  Therefore, while one may not want to put these patients through the 
toxicity of systemic multi-agent chemotherapy, there is certainly the feeling 
that something further must be done.  This group of untreated patients with 
intact bladders provides an ideal opportunity to explore new agents and 
collect tissue specimens to measure candidate prospective markers of 
response, receptor phosphorylation, and other downstream targets of 
biological agents.   
Use of the pT0 rate has been a well-established surrogate for activity and 
outcome in the setting of neoadjuvant therapy, and has been employed by 
our bladder trials group for over a decade of research.  Evidence suggests 
that patients who achieve this surrogate have the highest rates of overall 
survival, compared to those who do not achieve this clinical endpoint. 
 
Biologic Endpoint Rationale 
In addition to the main clinical endpoint, biologic hypotheses will be tested in 
the studies proposed as part of this trial. The first is that quantification of 
markers of EMT (E-cadherin, HER-4, and PDGFR-β), and correlation with 
changes in Ki-67, will allow us to prospectively identify tumors likely to 


Protocol 2007-0704 
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11 
respond to EGFR-directed therapy. The second is that changes in the 
expression of active EGFR, cyclin D1, p27, and KI-67 will identify those which 
are biologically responding to EGFR-directed therapy. The third is that tumor 
cell death may result from either direct effects on tumor cells or indirect 
effects of angiogenesis inhibition, so we will also assess the 
pharmacodynamics of angiogenesis inhibition by measuring the pro-
angiogenic factors VEGF and IL-8 as well as MVD, pericyte coverage, and 
endothelial cell apoptosis by laser scanning cytometry. These studies are 
important to determine whether angiogenesis inhibition occurs within the 
same tumors that display growth arrest; it is certainly possible that 
angiogenesis inhibition occurs more broadly or less frequently than growth 
arrest, which could have important implications for the early 
pharmacodynamic assessment of biological benefit from therapy.  
 
Serum and urine levels of MMP-9, IL-8, bFGF, and VEGF will be collected at 
baseline, weekly (± 3 days) during treatment, prior to cystectomy, following 
cystectomy, and at the first routine follow-up visit. 
 
In vitro studies suggest that microRNAs are regulators of tumor phenotypes 
and therapeutic response in bladder cancer. We will also measure free 
circulating microRNAs in serum or plasma, and in tissue specimens and 
correlate their expression with protein makers of biologic response, including 
Ki67, PCNA, and TUNEL. We will also correlate microRNAs to other protein 
markers related to EGFR sensitivity: ZEB2, ERRF-1, ZEB1, E-cadherin, and 
TGFalpha. By intercorrelating their results, we hope to derive a 
comprehensive tumor signature discriminating between EGFR sensitive and 
resistant tumor. 
 
The overall scientific objective is to define the molecular profile of urothelial 
carcinoma that responds to EGFR-targeted therapy. Additionally, we will also 
isolate mRNA, total RNA and microRNA from pre- and post-treatment 
biopsies for analysis on Affymetrix microarrays, using the institutional core 
facility (PI: Mini Kapoor, Ph.D.).  Ultimately, we hope to use the knowledge 
gained from this descriptive study to identify appropriate patients for EGFR-
directed or other selective targeted therapies. 
 
 
3.3 
SAFETY PLAN 
3.3.1 ADVERSE EVENTS USING TARCEVA 
Common adverse events associated with Tarceva administration include rash 
and diarrhea.  Other common adverse events include nausea/vomiting, 
mucositis/stomatitis, headache, and fatigue.  


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A rash occurred in 75% of Tarceva-treated NSCLC patients enrolled in 
BR.21.  Similar incidence of rash have occurred when erlotinib was 
administered concurrently with chemotherapy including gemcitabine, 
paclitaxel/carboplatin, and gemcitabine/cisplatin.  A papular, pustular rash 
manifesting most often on the face and upper trunk was common across all 
studies, but rash was rarely the cause of study drug discontinuation. Other 
dermatologic manifestations reported in clinical studies or postmarketing use 
of Tarceva include nail changes, paronychia, painful fissures or cracking of 
the skin on the hands and feet, and hair growth abnormalities (alopecia, 
thinning hair, eyelash/eyebrow changes, hirsutism). 
Wearing of contact lenses while receiving Tarceva therapy is not 
recommended.  The incidence of diarrhea in BR.21 was 54% of Tarceva-
treated NSCLC patients.  The median time to onset of skin rash was 8 days 
and median time to occurrence of first diarrheal symptom was 9 days.  
There have been infrequent reports of serious (including fatal) interstitial lung 
disease (ILD) in patients receiving Tarceva for treatment of NSCLC or other 
advanced solid tumors.  In Study BR.21, the incidence of ILD (0.8%) was the 
same in the placebo and Tarceva groups.  The overall incidence in Tarceva-
treated patients from all studies (including uncontrolled studies and studies 
with concurrent chemotherapy) is approximately 0.6%.  Included in this rate of 
ILD are reported diagnoses of pneumonitis, radiation pneumonitis, 
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, 
obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress 
syndrome, alveolitis, and lung infiltration, irrespective of investigator assessed 
causality.  Most of the cases were associated with confounding or contributing 
factors such as concomitant/prior chemotherapy, prior radiotherapy, 
preexisting parenchymal lung disease, metastatic lung disease, or pulmonary 
infections. 
Rare cases of acute renal failure or renal insufficiency have been reported 
(including fatalities).  Many of these cases have been associated with 
dehydration associated with nausea, vomiting, diarrhea, and/or anorexia.  
There have been rare reports of renal failure in patients receiving Tarceva in 
combination with platinum-containing chemotherapy regimens. Febrile 
neutropenia has been reported in patients receiving concomitant 
chemotherapy.   
Tarceva is both protein bound (92%–95%) and metabolized by hepatic 
cytochromes CYP3A4 and CYP3A5 and pulmonary cytochrome CYP1A1.  
Therefore, a potential for drug–drug interaction exists when Tarceva is 
co-administered with drugs that are highly protein bound or that are CYP3A4 
inhibitors/inducers.   
Co-administration of Tarceva with omeprazole, a proton pump inhibitor, 
decreased the exposure of Tarceva (AUC) by 46% and the maximum 


Protocol 2007-0704 
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13 
concentration (Cmax) by 61%. There was no change to Tmax or half-life.  
Therefore, drugs that alter the pH of the GI tract may alter the solubility of 
Tarceva and hence its bioavailability. 
The exposure to Tarceva (AUC) increased to a moderate extent, by 39%, and 
the maximum concentration (Cmax) by 17%, when Tarceva was co-
administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2. 
Co-administration of Tarceva with an inhibitor of CYP3A4 metabolism 
(ketoconazole, 200 mg po BID for 5 days) resulted in increased exposure to 
Tarceva as measured by an 86% increase in median Tarceva AUC and a 
69% increase Cmax, compared with administration of Tarceva alone. 
Induction of CYP3A4 metabolism by a known enzyme inducer (rifampin, 
600 mg po QD for 7 days) resulted in a 69% decrease in the median Tarceva 
AUC, compared with administration of Tarceva alone.  However, the effect of 
rifampin on Cmax was negligible.  In another study, rifampicin pretreatment 
followed by co-administration of rifampicin with a single 450 mg dose of 
Tarceva resulted in a mean Tarceva exposure (AUC) that was 57.6% of that 
observed following a single 150 mg Tarceva dose in the absence of rifampicin 
treatment.  Therefore, a potential for drug-drug interaction exists when 
Tarceva is co-administered with drugs that are highly protein bound or that 
are potent CYP3A4 inhibitors or inducers. 
International normalized ratio (INR) elevations and/or bleeding events have 
been reported in some cancer patients while on Tarceva alone and in 
combination with other chemotherapeutic agents, and concomitant NSAIDS 
or anticoagulants, including warfarin. 
3.3.2 General Plan to Manage Safety Concerns 
A number of measures will be taken to ensure the safety of patients 
participating in this trial, addressed through exclusion criteria and routine 
monitoring.  Patients will be evaluated for adverse events at each study visit 
for the duration of their participation in the study and for 30 days after the 
discontinuation of Tarceva.  
Skin toxicities will be monitored by routine physical examination and managed 
symptomatically.    The following agents may be used to treat rash:  
diphenhydramine, topical or oral corticosteroids, and topical (clindamycin) or 
oral antibiotics (tetracycline, minocycline, doxycycline).  Topical drying agents 
are not recommended.   
Diarrhea will be monitored and managed symptomatically.  Guidelines for 
management include administration of loperamide and Tarceva dose 
reduction/interruption as described in Section 4.3.3 and Table 2. 
Although quite rare, ILD can be life threatening.  Therefore, patients should 
be monitored closely for symptoms consistent with ILD, such as new onset 


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14 
dyspnea without an obvious cause.  In the event that ILD is suspected, 
Tarceva treatment should be discontinued and the patient should receive 
appropriate medical management.  Although there is no proven therapy, 
systemic corticosteroids are often provided.  Tarceva should not be restarted 
in those patients suspected of having drug-related ILD.  See Section 4.3.3 
and Table 2 for management guidelines, including Tarceva dose interruption. 
Liver function abnormalities, including elevated serum ALT, AST, and/or 
bilirubin, have been observed infrequently with single-agent Tarceva and 
occasionally with Tarceva in combination with concomitant chemotherapy.  
Periodic monitoring of liver function is recommended.  Tarceva dosing should 
be interrupted if changes in liver function are severe. 
Women of childbearing potential should have a negative pregnancy test prior 
to starting therapy with Tarceva and should use adequate contraceptive 
methods during and for at least 2 weeks after Tarceva therapy.    Treatment 
should only be continued in pregnant women if the potential benefit to the 
mother outweighs the risk to the fetus.  If Tarceva is used during pregnancy, 
the patient should be apprised of the potential hazard to the fetus or potential 
risk for loss of the pregnancy. 
It is not known whether Tarceva is excreted in human milk.  Because many 
drugs are excreted in human milk and because the effects of Tarceva on 
infants have not been studied, women should be advised against breast-
feeding while receiving Tarceva therapy. 
 
3.4 
ADMINISTRATIVE STRUCTURE 
This is a single institution, investigator sponsored trial performed with the 
approval of Genentech, Inc. and OSI Pharmaceuticals. 
The Department of Genitourinary Medical Oncology will manage this single 
institution trial along with the infrastructure of the Office of Protocol Research.  
The trial will follow all MD Anderson Cancer Center Institutional Review Board 
(IRB) guidelines and policies. 
The current requirements of the department include a full time Quality 
Assurance Program with standard operating procedures (SOP), orientation, 
as well as staff development.  According to the Cancer Therapy Evaluation 
Program (CTEP), quality assurance includes prevention, detection and action 
from the beginning of the clinical trial to true completion with analysis and 
manuscript meeting the overall objectives.   
The Quality Assurance program of the Department of Genitourinary (GU) 
Medical Oncology has been designed to verify compliance with the protocol 
and regulatory requirements, and identify learning needs of the research staff. 


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15 
The Departmental program is a supplement the ORERM, and is in alignment 
with the institutional goals.   
 
3.5 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study must be conducted in compliance with the protocol and according 
to Good Clinical Practice as described in the following documents: 
The MD Anderson Cancer Center IRB 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996 
US Code of Federal Regulations dealing with clinical studies (21 CFR 
including parts 50 and 56 concerning informed consent and IRB regulations) 
 
MDA Policy:  All protocols involving human subjects will be reviewed and 
approved by an MDACC Institutional Review Board prior to commencing the 
research.  
 
45 CFR §46.109 (a) An IRB shall review and have authority to approve, 
require modification in (to secure approval), or disapprove all research 
activities covered by this policy. 
45 CFR §46.109 (d)  An IRB shall notify investigators and the institution in 
writing of its decision to approve or disapprove the proposed research activity, 
or of modifications required to secure IRB approval of the research activity.  If 
the IRB decides to disapprove a research activity, it shall include in its written 
notification a statement of the reasons for its decision and give the 
investigator an opportunity to respond in person or in writing. 
21 CFR §56.109 (a)  An IRB shall review and have authority to approve, 
require modifications in (to secure approval), or disapprove all research 
activities covered by these regulations. 
21 CFR §56.109 (e)  An IRB shall notify investigators and the institution in 
writing of its decision to approve or disapprove the proposed research activity, 
or of modification required to secure IRB approval of the research activity.  If 
the IRB decides to disapprove a research activity, it shall include in its written 
notification a statement of the reasons for its decision and give the 
investigator an opportunity to respond in person or writing. 
The informed consent process begins when a potential research participant is 
initially contacted regarding a study by the investigator or his staff. 
Participants should not be approached about a potential protocol prior to that 
study being approved by the Institutional Review Board (IRB). 


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The attending physician shall be responsible for ensuring that the informed 
consent process is documented by the use of a written consent form 
approved by the IRB and signed by the participant or participant’s legally 
authorized representative (unless this requirement is specifically waived by 
the IRB).  
Upon activation, each page of the informed consent document is imprinted 
with the “IRB Approved Consent” stamp. The stamp is signed and dated by 
the assigned protocol compliance specialists and distributed to the principal 
investigator. Additional copies must be made and distributed by the 
department.  Consents that are submitted in PDOL will be available on-line 
following activation. 
Only the most recent version of the informed consent document approved by 
the IRB should be used when addressing new participants.  The date 
stamped on the informed consent document should correspond with the 
informed consent date in the Protocol Data Management System 
(PDMS)/Clinical Oncology Research System (CORe) during the registration 
process, verifying that the correct version of the document has been signed.  
Consents for protocols that are available on-line through PDOL, will have the 
most recent revision date typed on the lower right-hand corner of the 
document. 
Informed consent must be obtained prior to the initiation of any protocol-
specific screening procedures that are not considered standard of care. 
 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 INCLUSION CRITERIA  
Patients must fulfill all of the following criteria to be eligible for study entry: 
1. Patients must have histologic proof of urothelial cancer.  This includes 
bladder cancer, in addition to other tumors of the urothelial lining including 
renal pelvis, ureteral, and urethral cancer. This group may include any 
patient requiring cystectomy, including patients with recurrent or extensive 
superficial disease (cTa-T1N0M0), CIS (carcinoma in situ), or muscle 
invasive disease (cT2-3aN0M0), whose tumor could not be completely 
removed at transurethral resection. 
2. Patients with the following high-risk features:  Micropapillary features 
(more than focal on pathology); Small cell carcinoma; 3-D mass on exam 
under anesthesia (EUA); Lymphovascular invasion; Hydronephrosis 
(unless in the opinion of the treating physician, this is not due to tumor); 
High grade (grade 3) tumors of the ureter, renal pelvis, or urethra, or 


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17 
tumors in these areas with radiographic abnormality large enough to 
recognize as an abnormal mass by CT or MRI imaging; Direct invasion of 
the prostatic stroma or the vaginal wall (ie: cT4a disease) should be 
offered neoadjuvant cytoreductive chemotherapy (ie: cisplatin-based).   
Patients refusing or who are not considered candidates for cytoreductive 
chemotherapy may be considered eligible.  Dr. Siefker-Radtke will be the 
final arbiter in determining eligibility for the trial. 
3.  
4. Please note that the presence of variant histologic subtypes is acceptable, 
except in the case for small cell variant which is traditionally treated with 
cytoreductive chemotherapy.  Patients with small cell who refuse 
recommended cytoreductive chemotherapy may still be considered 
eligible. 
5. Patients must have an evaluation in the department of urology, and be 
deemed an acceptable surgical candidate. 
6. Patients must NOT have clinical evidence of metastatic disease by either 
CT or MRI of the abdomen and pelvis, and chest x-ray.  In the absence of 
a bone scan, patients should be free of bone pain and have an alkaline 
phosphatase < 1.5 x ULN of the upper limit of normal, or a normal bone 
fraction of alkaline phosphatase.  If these features are present, patients 
should have a bone scan and this should be interpreted as showing no 
evidence of metastatic disease in order to be eligible. 
7. Individuals must be > 18 years of age.  In general, urothelial cancer occurs 
in the 6th to 7th decade of life, so it is unlikely that pediatric patients will be 
included. 
8. Patients, all 18 years and older, must either be not of child bearing 
potential or have a negative pregnancy test within 2 weeks of treatment. 
Patients are considered not of child bearing potential if they are surgically 
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or they are postmenopausal. 
9. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,000/ul; 
platelets ≥ 75,000/μl. 
10. Renal function: creatinine ≤ 2.0 x institutional upper limit of normal (ULN), 
or a creatinine clearance of ≥ 30 ml/min as calculated by Cockroft-Gault or 
by 24-hour urine collection.  
11. Hepatic function: bilirubin ≤ 2.5 x ULN; AST ≤ 5.0 x ULN. 
12. Zubrod PS ≤ 2. 
13. Patients with second malignancies are eligible provided that the expected 
outcome from the second cancer is such that this will not interfere in the 


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delivery of this therapy, or in doing cystectomy, and provided that the 
expectation of survival from any prior malignancy is reliably > 4 years. 
 
4.1.2 EXCLUSION CRITERIA 
Patients meeting any of the following criteria are ineligible for study entry: 
1. Acute hepatitis or known HIV. 
2. Active or uncontrolled infection. 
3. Significant history of uncontrolled cardiac disease; i.e., uncontrolled 
hypertension, unstable angina, recent myocardial infarction (within prior 6 
months), uncontrolled congestive heart failure, and cardiomyopathy with 
decreased ejection fraction ≤ 40%. 
4. Prior therapy specifically and directly targeting the EGFR pathway (i.e.: 
erlotinib, gefitinib, and cetuximab). 
5. Patients with interstitial lung disease. 
6. Any concurrent chemotherapy not indicated in the study protocol or any 
other investigational agent(s). 
7. Patients with metastatic or surgically unresectable disease are not eligible 
for this study.  In addition, patients who do not agree to surgery are not 
eligible for this trial. 
8. Patients who have received prior systemic chemotherapy or radiation 
therapy for urothelial cancer are not eligible.  Any prior intravesical 
chemotherapy is allowed. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
All patients will receive daily Tarceva.  There is no randomization planned, 
and no placebos will be used.  Since this is a single-armed trial, consecutively 
eligible patients will be offered enrollment.  
 
4.3 
STUDY TREATMENT 
4.3.1 Formulation 
Tarceva oral tablets are conventional, immediate-release tablets containing 
erlotinib as the hydrochloride salt. In addition to the active ingredient, Tarceva 
contains lactose (hydrous), microcrystalline cellulose, sodium starch 
glycolate, sodium lauryl sulfate, and magnesium stearate.   


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19 
Tablets containing 25 mg, 100 mg, and 150 mg of Tarceva are available. 
Each bottle will contain 30 tablets, a quantity sufficient for 4 consecutive 
weeks of dosing, with overage.   
For further details, see the Tarceva Investigator’s Brochure. 
 
4.3.2 Dosage, Administration, and Storage 
Tarceva will be self-administered in an open-label, unblinded manner to all 
patients enrolled in the study. During the treatment period, patients will 
receive single-agent Tarceva, 150 mg/day.  Tablets should be taken at the 
same time each day with 200 mL of water at least 1 hour before or 2 hours 
after a meal.  Patients who are unable to swallow tablets may dissolve the 
tablets in distilled water for administration. 
Dose reductions for adverse events will be permitted (see Section 4.3.3).  
Treatment is continued daily until disease progression or other reason for 
termination of study therapy (see Section 4.7). 
Tarceva tablets will be supplied for clinical trials in white, high-density 
polyethylene (HDPE) bottles with child-resistant closures and should be 
stored at temperatures between 15°C and 30°C (59°F and 86°F). 
 
4.3.3 Dose Modification  
Dose reduction or interruption of Tarceva for toxicity may take place at any 
time during the study.  Toxicity grading is based on NCI-CTCAE, v 3.0.  Dose 
level reductions are presented in Table 1.  If patients do not tolerate the 
second dose reduction, Tarceva is to be discontinued.  
 
Table 1  
Tarceva Dose Level Reductions 
Starting Dose  
First Reduction 
Second Reduction 
150 mg/day 
100 mg/day 
50 mg/day 
Dose modification guidelines are summarized in Table 2.  
Management of a tolerable Grade 2 or 3 rash should include continuation of 
Tarceva at the current dose and symptomatic management.  If skin rash is 
intolerable, dose reduction according to Table 2 should be considered.  When 
skin toxicity improves by at least one grade level, the dose may be 
re-escalated as tolerated.  In Phase II trials, this approach enabled dose 
re-escalation for the majority of patients requiring dose reduction for skin 


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20 
toxicity.  Patients experiencing Grade 4 skin toxicity should be discontinued 
from study treatment.     
For Grade 1 or 2 diarrhea, early intervention should include continuation of 
Tarceva at the current dose and initiation of loperamide therapy as described 
in Table 2.  Grade 2 diarrhea that persists over 48–72 hours, despite optimal 
medical management, should be managed by dose reduction according to 
Table 2.  Patients experiencing Grade 3 diarrhea should interrupt Tarceva 
until resolution to Grade ≤1 and re-start at a reduced dose according to Table 
2.  Patients should be maintained at the reduced dose without attempt at 
dose re-escalation.  Patients experiencing Grade 4 diarrhea should be 
discontinued from study treatment. 
Tarceva should not be restarted in those suspected of having drug-related 
ILD. 
 


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Table 2 
Dosage Modification Criteria and Guidelines for Management  
of Tarceva-Related Toxicities 
NCI-CTCAE (v 3.0) Grade 
Tarceva Dose Modification 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg at 
first onset, followed by 2 mg q 
2–4 hours until free of diarrhea 
for 12 hours) 
Grade 2 
None 
(Dose reduction of Tarceva is 
necessary if diarrhea persists 
over 48–72 hours despite 
optimal medical management) 
Loperamide (4 mg at first onset, 
followed by 2 mg q 2–4 hours 
until diarrhea free for 12 hours) 
Grade  3 
Interrupt then dose reduce 
Tarceva.  Tarceva should not be 
re-escalated. 
Interrupt Tarceva until 
resolution to Grade ≤1, and 
restart at next reduced dose 
Grade 4 
Discontinue study treatment. 
 
Pulmonary Events if possibly ILD 
All Grades 
Temporarily interrupt Tarceva 
pending the diagnostic 
evaluation.  If the pulmonary 
adverse event is assessed as 
related to Tarceva, discontinue 
the patient from study treatment. 
Unexplained dyspnea, either 
new or progressive, should be 
aggressively evaluated.   
Rash 
Grade 1 and 2 
Tolerable rash 
None 
Any of the following: oral 
antibiotics (tetracycline, 
minocycline, doxycycline) 
topical clindamycin, 
diphenhydramine, topical or oral 
corticosteroids at discretion of 
investigator 
Grade 3 
Intolerable rash 
Consider interruption and or 
dose reduction if unresponsive to 
symptomatic management.  
Re-escalation is allowed. 
Manage as described above 
Grade 4 
Discontinue study treatment. 
Manage as described above 
 
 
 
4.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Use of anti-neoplastic or anti-tumor agents not part of the study therapy, 
including chemotherapy, radiation therapy, immunotherapy, and hormonal 
anticancer therapy, is not permitted while participating in this study.  


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Use of concurrent investigational agents is not permitted. 
There are potential interactions between Tarceva and CYP3A4 inhibitors and 
CYP3A4 promoters.  Although caution and careful monitoring are 
recommended when use of these compounds is necessary, use of these 
compounds does not exclude patients from participating in this trial (see 
Appendix B for a list of CYP3A4 inhibitors and inducers). 
Grapefruit juice is a CYP3A4 inhibitor, therefore, consumption of grapefruit or 
grapefruit juice should be avoided during Tarceva treatment. 
The solubility of Tarceva is pH dependent.  Tarceva solubility decreases as 
pH increases. Co-administration of Tarceva with omeprazole, a proton pump 
inhibitor, decreased the exposure of Tarceva (AUC) by 46% and the 
maximum concentration (Cmax) by 61%.  There was no change to Tmax or 
half-life.  Therefore, drugs that alter the pH of the GI tract may alter the 
solubility of Tarceva and hence its bioavailability. 
The exposure to Tarceva (AUC) increased to a moderate extent, by 39%, and 
the maximum concentration (Cmax) by 17%, when Tarceva was co-
administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2. 
Tarceva clearance can be induced by smoking via CYP1A2 induction. 
Potential drug-drug interaction is expected when Tarceva is taken with 
CYP1A2 inducers or inhibitors.  In a single-dose study in healthy volunteers, 
the AUC was reduced by 64% in smokers when compared with nonsmokers.  
In BR.21, current smokers achieved Tarceva trough plasma concentrations 
that were approximately 2-fold lower than never smokers.  Smokers should 
be advised to stop smoking while taking Tarceva as plasma concentrations of 
Tarceva are reduced due to the effect of cigarette smoking. 
Pretreatment or co-administration of Tarceva did not alter the clearance of a 
prototypical CYP3A4 substrate, midazolam.  Therefore, significant metabolic 
interactions with other CYP3A4 substrates are unlikely.  However, the oral 
bioavailability of midazolam decreased by up to 24% following Tarceva 
treatment, which was not attributed to a metabolic interaction. 
Patients taking warfarin or other warfarin-derivative anticoagulants should be 
monitored regularly for changes in prothrombin time or INR. 
 
 
 
4.5 
STUDY ASSESSMENTS (SEE APPENDIX 1) 
 


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4.5.1 SCREENING AND PRETREATMENT ASSESSMENTS 
Patients should have a history and physical examination.  All patients must be 
seen by a Urologic Surgeon at M. D. Anderson and have a cystoscopy and 
exam under anesthesia (EUA) prior to registration.  (Please note, an EUA is 
only done in the setting of urothelial tumors of the bladder). 
 
Laboratory studies: CBC with platelets and automated differential, 
electrolytes, magnesium, calcium, albumin, LDH, AST (or ALT), alkaline 
phosphatase, total bilirubin, creatinine, and BUN.  Patients should have a 
prothrombin time if they have not yet had a cysto/EUA. These studies should 
be obtained within 3 weeks of study entry. 
 
Other baseline studies required at study entry: chest x-ray (within 6 weeks), 
EKG (within 6 months), CT (or MRI) of the abdomen and pelvis within 6 
weeks of study entry.  Since the bone scan is known to be falsely negative in 
a high percentage of cases and is not routinely done in this setting, patients 
are not required to have a bone scan unless they meet alkaline phosphatase 
or pain criteria as listed in the inclusion criteria. 
 
Tissue/specimen collection:  Cancer tissue will be obtained during 
cystoscopy (or from archived specimens) and transurethral resection of 
bladder tumor during routine staging procedures.  Tissue following treatment 
will be obtained at cystectomy  
 
We will also record the time at which the vascular pedicles of the bladder are 
ligated so we can determine the correlation between ischemic time and 
integrity of these phosphorylated proteins.  Immunohistochemical staining be 
performed include EGFR, phospho-EGFR, PCNA, CD31, TUNEL, 
AKT/phospho-AKT, MAPK, and GSK3B.  Other markers will be evaluated if 
appropriate. 
 
Serum and urine levels of MMP-9, IL-8, bFGF, and VEGF will be collected at 
baseline, weekly (± 3 days) during treatment, prior to cystectomy, following 
cystectomy, and at the first routine follow-up visit. 
 
Pathology specimens and serum and urine samples derived by surgical or 
other procedures during standard patient care will be stored in the Bladder 
SPORE tissue bank.  Tissue will be appropriately annotated/dated.  Requests 
for tissue will be preferentially used for (1) clinical care, (2) meeting the 
endpoints of this trial.  Additional samples remaining will be made available to 
investigators interested in studying important molecular targets that may be 
predictive of outcome or provide additional insight into the mechanism of 
action of Tarceva or the biology of transitional cell urothelial tumors.  Samples 


Protocol 2007-0704 
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24 
will be collected and stored as per institutional guideline.  All requests must 
be in the context of IRB approved protocols. 
 
4.5.2 EVALUATIONS AND PROCEDURES DURING TREATMENT  
All patients will be seen weekly (± 3 days) while on Tarceva by the physician 
or their designee (research nurse, advance practice nurse, physician 
assistant, nurse practitioner, clinic nurse) to evaluate for toxicity.  Patients will 
have weekly (± 3 days) CBC with platelets, AST or ALT, serum Cr, and 
electrolytes.  
 
4.5.3 TREATMENT DISCONTINUATION ASSESSMENTS  
Patients discontinuing treatment for toxicity, will be seen every other week by 
the physician or their designee (research nurse, advance practice nurse, 
physician assistant, or nurse practitioner) to document improvement, until the 
time of surgery.  Patients discontinuing treatment by choice alone (ie: in the 
setting of no toxicity), will not be required to follow weekly. 
 
4.5.4 FOLLOW-UP ASSESSMENTS 
Patients should be seen in the clinic or contacted by telephone to determine if 
any serious or non-serious adverse events have occurred within 30 days 
(± 3 days) of termination of Tarceva dosing. 
Patients will have routine post-surgical follow-up after cystectomy as 
determined by their urologist.  Long-term follow-up, including CT of the 
abdomen and pelvis, CXR, and laboratory tests will be done as determined by 
the treating physician.  Long-term follow up will be done every 6 months for 
the first year, followed by yearly intervals for the next 4 years.  Follow-up may 
be done more frequently based upon the pathologic stage/discretion of the 
treating physician.  Patients may go on to adjuvant chemotherapy if deemed 
appropriate by their treating physician.  They will continue to be followed for 4 
years. 
 
4.6 
ASSAY METHODS  
Patients will be treated with daily Tarceva for 3 weeks, followed by 
cystectomy (or ureterectomy/nephrectomy/urethrectomy).  The last dose of 
Tarceva will be given within 24 hours prior to scheduled surgical time. 
Patients will have tissue collected at baseline, prior to Tarceva, as part of 
staging cystoscopy (or from archived specimens), and will have residual 
tumor tissue collected at the time of cystectomy (or 
ureterectomy/nephrectomy).  Blood and urine specimens will also be 


Protocol 2007-0704 
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25 
collected at baseline, weekly (± 3 days) while on treatment, at cystectomy, 
and at the first restaging follow-up visit (usually within 3-6 months). 
 
Markers of the epithelial to mesenchymal transition (EMT) (ie: E-cadherin, 
ZEB1, ZEB2, ERRF-1, TGFα, HER4, PDGFR-beta, vimentin, and fibronectin) 
will be analyzied in pre- and post-treatment biopsies to correlate expression 
patterns with clinical response (ie pT0 rate) and biological response and 
target inhibition.   EMT expression patterns will be correlated with markers of 
anti-proliferation (KI-67), apoptosis (TUNEL) and angiogenesis (two-color 
TUNEL, phosphor-receptor, and microvessel density).  EGFR copy number 
and mRNA expression in pre and post-treatment biopsies using Affymatrix 
arrays and tumor tissue and serum microRNAs and Total RNA will also be 
correlated with changes with changes observed with EMT, growth arrest, and 
apoptosis. To provide further insight into biology, we will also interrogate 
membrane (phosphorylated EGFR) and downstream receptor signaling 
pathways (ERKs, AKT.mTOR, GSK-3beta). 
 
4.7 
PATIENT DISCONTINUATION 
Patients may discontinue study treatment at any time.  Any patient who 
discontinues treatment will be encouraged to return to the study center to 
undergo treatment discontinuation assessments.  The primary reason for 
discontinuation should be recorded.  Reasons for discontinuation of a patient 
by the investigator include, but are not limited to, the following:   
• Documented disease progression    
• Clinically significant deterioration of the patient’s condition prior to 
treatment discontinuation  
• Patient noncompliance 
• Persistent (≥ 3 weeks) NCI-CTCAE version 3.0 Grade 3 or Grade 4 
adverse event or any significant adverse event that compromises the 
patient’s ability to participate in the study  
• Investigator determination that it is not in the patient’s best interest to 
continue participation 
• Pregnancy 
• Patient Decision 
 
 


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26 
4.8 
STATISTICAL METHODS 
Determination of Sample and Monitoring for Efficacy 
Sample Size: Clinical Endpoint 
 
Assume the baseline response (pT0 rate) to be 10%, and an increase of the 
response rate to 25% after the neoadjuvant therapy. With type I and type II error 
rates of 0.1 and 0.1, we need a maximum number of 40 patients for the Simon’s 
Min-max two-stage design. At the first stage of the trial, if there are 2 or less 
responses observed among the first 27 patients, the trial should be terminated and 
the treatment will not be considered for further study. If there are at least 3 
responses observed among the first 27 patients, 13 more patients will be enrolled in 
the second stage for a total of 40 patients. If at least 7 responses are observed from 
all 40 patients, the treatment will be considered for further investigation.  To take into 
consideration of possible unevaluable patients in assessing the biologic endpoints, 
we plan on accruing a total of 42 patients. 
 
Safety Endpoints and Monitoring: 
Toxicity outcomes will be monitored periodically for patients after the treatments. 
Termination will be recommended if it is very likely that the surgery-limiting toxicity 
rate has exceeded 15%. For this trial, surgery-limiting toxicity will be defined as 
hemorrhage requiring major non-elective intervention or wound dehiscence (defined 
as fascial disruption with evisceration) within 30 days post-operatively. [Formally, 
stop if Prob (θ > 0.15) ≥ 0.80, where θ refers to the toxicity rate for the investigated 
regimen. The prior distribution on θ is Beta(.1, .9)]. The trial will be terminated if the 
following stopping boundaries are crossed:  
 
Number of patients 
Stop trial  if number of toxicity greater than or equal to 
5 
2 
10 
3 
15 
4 
20 
5 
25 
6 
30 
7 
35 
8 


Protocol 2007-0704 
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27 
40 
9 
 
Note that the trial may be terminated prior to reaching the specified number of 
patients in a cohort. For example, if there are two patients with toxicity among the 
first 3 patients, the trial will be terminated for excessive toxicity.  
 
A simulation study was conducted to examine the property of the stopping rule under 
a variety of scenarios (10,000 simulated trials per scenario). The following table 
summarizes the probability of stopping the trial early due to toxicity and the expected 
sample size for the indicated true toxicity rate:  
 
percentage of sample size 
True toxicity rate 
Prob(stop early) 
25% 
50% 
75% 
0.05 
0.03 
40 
40 
40 
0.10 
0.15 
35 
40 
40 
0.15 
0.37 
10 
40 
40 
0.20 
0.62 
5 
20 
40 
0.25 
0.82 
5 
10 
20 
0.30 
0.93 
5 
10 
15 
 
Moreover, the operating characteristics of the joint monitoring rules for both efficacy 
and toxicity are provided in the following table under the assumption that the two 
distributions are independent to each other. The true response rates are listed in the 
first row, and the true toxicity rates in the first column. The marginal probability that 
the trial is terminated at the first stage for futility is shown in the second row, while 
the toxicity is not considered.  
 
Tox/Resp 
0.1 
0.2 
0.25 
0.3 
0.35 
0 
0.48 
0.07 
0.02 
0.005 
0.001 
0.05 
0.496 
0.098 
0.049 
0.035 
0.031 
0.1 
0.558 
0.21 
0.167 
0.154 
0.151 
0.15 
0.672 
0.414 
0.383 
0.373 
0.371 
0.2 
0.802 
0.647 
0.628 
0.622 
0.62 
0.25 
0.906 
0.833 
0.824 
0.821 
0.82 
0.3 
0.964 
0.935 
0.931 
0.93 
0.93 
 


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28 
4.8.1 Analysis of the Conduct of the Study 
Methods for detection of violations of enrollment criteria, major protocol 
violations and deviations can be found in section 6.5.  Reasons for patient 
discontinuation from the study will be documented, as per section 4.7 
 
4.8.2 Analysis of Demographic and Baseline Characteristics 
Demographic characteristics will be collected at baseline.  These should 
included age, gender, Zubrod performance status, date of initial diagnosis, 
any prior treatment including resection and prior intravesical therapy. 
Descriptive analysis will be performed.  
 
4.8.3 Efficacy Analysis 
The primary endpoint of this trial is to estimate the response rate (ie: pT0 
rate) of patients with urothelial cancer treated with erlotinib prior to 
cystectomy.  In this context, response will be defined as the absence of 
residual cancer in the resected specimen. Since this is a single institution 
study, all specimens will be reviewed by a genitourinary pathologist in the 
department of pathology at M. D. Anderson Cancer Center. 
Use of the pT0 rate has been a well-established surrogate for activity and 
outcome in the setting of neoadjuvant therapy, and has been employed by 
our bladder trials group for over a decade of research.  Evidence suggests 
that patients who achieve this surrogate have the highest rates of overall 
survival, compared to those who do not achieve this clinical endpoint. 
A secondary objective is to estimate the 4-year disease-free survival of 
patients with urothelial cancer treated with erlotinib prior to cystectomy. 
An interim analysis will be performed after the first 27 patients.  If there are 2 
or less responses among the first 27 patients, the trial will be terminated.  If 
there are 3 or more responses, the trial will continue accrual. 
Full details regarding the analysis plans can be found in section 4.9.7 
 
4.8.4 Safety Analysis 
Patients will be monitored for toxicity using NCI CTCAEv3.0.  Toxicity will be 
monitored at the weekly (± 3 days) visits while on therapy.  Dose reductions 
based upon toxicity can be found in section 4.3. 
Surgery will not be delayed for missed Tarceva doses.  Patients who miss a 
dose of Tarceva may resume treatment if timing permits.  However, if the 
toxicity will interfere with or delay surgery, Tarceva will be discontinued. 


Protocol 2007-0704 
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29 
Though treatment with this agent is generally expected to be well-tolerated, 
patients will be monitored for specific toxicities which would be of concern in 
the surgical setting.  For this trial, surgery-limiting toxicity will be defined as 
hemorrhage or wound dehiscence within 30 days post-operatively.  The 
statistics employing the early stopping rules can be found in section 4.8. 
 
4.8.5 Pharmacokinetic Analyses 
This will be a descriptive study and extent of target inhibition will be 
correlated with clinical outcomes, including tumor response. In this setting, 
a 50% decrease in KI-67 will serve as a measure of antiproliferation, with 
a sample size of 42, the response rate can be estimated within 15% of the 
true value with 95% confidence interval. In the initial phase of analysis, we 
will apply a univariate analysis for each of the markers:  E-cadherin, 
HER4, PDGFR-β, GSK3β, phosphorylation, cyclin D1, p27 and KI67 
expression. We will estimate the change in proportion of each marker 
expression after treatment with a 95% confidence interval. We will also 
evaluate correlations among these markers before and after the treatment.  
These events will be correlated with any effects of therapy on MVD, mean 
vessel volume, changes in the percentages of tumor pericytes, endothelial 
cells, or both, and tumor and stromal cell apoptosis. Extent of target 
inhibition (EGFR signaling) will be correlated with KI67 as an indicator of 
response, because the study design does not allow us to measure 
objective tumor response. Angiogenesis factor expression will be 
correlated with endothelial cell apoptosis and MVD. 
 
4.8.6 Missing Data 
Patients receiving at least 1 dose of study medication will be assessable for 
both response and toxicity.   Patients who come off study without having 
received any of the study therapy will be replaced.     
 
4.9 
DATA QUALITY ASSURANCE 
Clinical information regarding registration and off study will be entered to the 
Institutional required data base CORe and PDMS.  Clinical data for analysis 
will be entered to the departmental database GURU.  The Data Base 
Coordinator will work with the protocol specific team in order to generate 
reports for quality analysis. 


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30 
5. 
ASSESSMENT OF SAFETY 
The safety of Tarceva will be assessed through collection and analyses of 
adverse events (AEs) and laboratory tests.  These assessments will occur 
weekly (± 3 days) while on therapy. In addition, patients will be assessed for 
potential surgical toxicity occurring within 30 days of cystectomy.  Though this 
treatment is expected to be generally well-tolerated, specific therapy-limiting 
toxicity can be found in section 4.8. 
5.1 
SPECIFICATION OF SAFETY VARIABLES  
Safety assessments will consist of monitoring and recording protocol-defined 
adverse events (AEs) and serious adverse events (SAEs); measurement of 
protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug(s). 
Death as a result of disease progression is only to be assessed as efficacy 
measures and not as AEs or SAEs. 
 
5.1.1 Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational (medicinal) product or 
other protocol-imposed intervention, regardless of attribution. 
This includes the following: 
• AEs not previously observed in the patient that emerge during the 
protocol-specified AE reporting period, including signs or symptoms 
associated with urothelial cancer that were not present prior to the AE 
reporting period (see Section 5.2.1) 
• Complications that occur as a result of protocol-mandated 
interventions (e.g., invasive procedures such as biopsies) 
• If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other 
protocol-mandated intervention 
• Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period 
• Diagnoses and/or symptoms associated with urothelial cancer should 
be reported as AEs if they worsen or change in character.  Clinical 
progression of urothelial cancer should not be reported as an AE. 
 


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31 
5.1.2 Serious Adverse Events 
An AE should be classified as an SAE if: 
• It results in death (i.e., the AE actually causes or leads to death).  
• It is life threatening (i.e., the AE, in the view of the investigator, places the 
patient at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results 
in substantial disruption of the patient’s ability to conduct normal life 
functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the investigational product. 
• It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the patient or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
All AEs that do not meet any of the criteria for serious should be regarded as 
nonserious AEs. 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) 
refers to the grade of a specific AE, e.g., mild (Grade 1), moderate (Grade 2), 
or severe (Grade 3) myocardial infarction (see Section 5.2.2).  “Serious” is a 
regulatory definition (see previous definition) and is based on patient or event 
outcome or action criteria usually associated with events that pose a threat to 
a patient’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the Sponsor to applicable 
regulatory authorities.  
Severity and seriousness should be independently assessed when recording 
AEs and SAEs on the CRF. 
5.2 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study, as outlined in Section 5.1.1, are 
recorded on the CRF and reported to the Sponsor in accordance with protocol 
instructions.  
Death as a result of disease progression endpoints are only to be assessed 
as efficacy measures and not as AEs or SAEs. 
 


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32 
5.2.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins 
after informed consent is obtained and initiation of study treatment and ends 
30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier.  After this period, 
investigators should only report SAEs that are attributed to prior study 
treatment. 
SAEs that are observed or reported prior to initiation of study treatment 
should be recorded as SAEs on the CRF if they are associated with protocol-
mandated interventions (e.g., invasive procedures such as biopsies, 
medication washout, or no treatment run-in). 
 
5.2.2 Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all patient 
evaluation timepoints during the study.  All AEs and SAEs whether 
volunteered by the patient, discovered by study personnel during questioning, 
or detected through physical examination, laboratory test, or other means will 
be recorded in the patient’s medical record and on the appropriate AE or SAE 
CRF page. 
Each recorded AE or SAE will be described by its duration (i.e., start and end 
dates), severity (see Table 3), regulatory seriousness criteria if applicable, 
suspected relationship to the investigational product (see following guidance), 
and actions taken. 
The AE grading (severity) scale found in the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0, 
will be used for AE reporting. 
 


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33 
Table 3 
Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI-CTCAE grading criteria) 
Transient or mild discomfort 
(< 48 hours); no interference with the 
patient’s daily activities; no medical 
intervention/therapy required 
2 
Moderate (apply event-specific  
NCI-CTCAE grading criteria) 
Mild to moderate interference with the 
patient’s daily activities; no or 
minimal medical intervention/therapy 
required 
3 
Severe (apply event-specific  
NCI-CTCAE grading criteria) 
Considerable interference with the 
patient’s daily activities; medical 
intervention/therapy required; 
hospitalization possible 
4 
Very severe, life threatening,  
or disabling (apply event-specific NCI-
CTCAE grading criteria) 
Extreme limitation in activity; 
significant medical 
intervention/therapy required, 
hospitalization probable 
5 
Death related to AE 
 
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  Refer to 
definitions of an SAE (see Section 5.1.2). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI-CTCAE listing. 
 
To ensure consistency of AE and SAE causality assessments, investigators 
should apply the following general guideline: 
• YES 
There is a plausible temporal relationship between the onset of the AE and 
administration of the investigational product, and the AE cannot be readily 
explained by the patient’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to the 
investigational product; and/or the AE abates or resolves upon 
discontinuation of the investigational product or dose reduction and, if 
applicable, reappears upon re-challenge. 
• NO 
Evidence exists that the AE has an etiology other than the investigational 
product (e.g., preexisting medical condition, underlying disease, intercurrent 
illness, or concomitant medication); and/or the AE has no plausible temporal 


Protocol 2007-0704 
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34 
relationship to administration of the investigational product (e.g., cancer 
diagnosed 2 days after first dose of study drug). 
Note:  The investigator’s assessment of causality for individual AE reports is 
part of the study documentation process.  Regardless of the “Yes” or “No” 
causality assessment for individual AE reports, the Sponsor will promptly 
evaluate all reported SAEs against cumulative product experience to identify 
and expeditiously communicate possible new safety findings to investigators 
and applicable regulatory authorities. 
 
5.2.3 SAE Reporting Guidelines 
All STEAEs will be recorded on an MDACC Internal Adverse Event Form and 
faxed to: 
Genentech Drug Safety 
Fax: (650) 225-4682 or (650) 225-4683 
AND: 
Arlene Siefker-Radtke, M.D. 
MD Anderson Cancer Center 
1155 Pressler Street, Unit 1374 
Houston, TX 77030 
Follow-up information: 
Additional information may be added to a previously submitted report by 
completing a new MDACC Internal Adverse Event Form and indicating “F/U 
Follow-Up” in the appropriate field. 
Occasionally, Genentech may contact the reporter for additional information, 
clarification or current status of the subject for whom an adverse event was 
reported.  For questions regarding STEAE reporting, you may contact the 
Genentech Drug Safety representative noted above. 
5.3 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS 
5.3.1 Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all 
patient evaluation timepoints should be adopted.  Examples of non-directive 
questions include:  
 “How have you felt since your last clinical visit?” 


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35 
“Have you had any new or changed health problems since you were last 
here?” 
5.4 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS 
Investigators will submit written reports of all SAEs, regardless of attribution, 
to Genentech within 48 hours of learning of the events.  For initial SAE 
reports, investigators should record all case details that can be gathered 
within 48 hours.  The completed SAE form and SAE Fax Cover Sheet should 
be faxed immediately upon completion to Genentech’s Drug Safety 
Department at: 
(650) 225-4682 
or  
(650) 225-5288 
Relevant follow-up information should be submitted to Genentech’s Drug 
Safety as soon as it becomes available and/or upon request. 
 
5.5 
TYPE AND DURATION OF FOLLOW-UP OF PATIENTS AFTER ADVERSE 
EVENTS 
All AEs and SAEs that are encountered during the protocol-specified AE 
reporting period should be followed to their resolutions, or until the 
investigator assesses them as stable, or the patient is lost to follow-up.  
Resolution of AEs and SAEs (with dates) should be documented on the 
appropriate AE page and in the patient’s medical record to facilitate source 
data verification. 
For some SAEs, the Sponsor or its designee may follow-up by telephone, fax, 
electronic mail, and/or a monitoring visit to obtain additional case details 
deemed necessary to appropriately evaluate the SAE report (e.g., hospital 
discharge summary, consultant report, or autopsy report).  Contact 
information is as follows: 
PI: Arlene O. Siefker-Radtke, MD 
Assistant Professor of Genitourinary Medical Oncology 
1155 Hermann Pressler, Unit 1374 
Houston, TX  77030 
Phone: 713-792-2830 
Fax: 713-745-1625 
 


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36 
6 
SPONSOR AND INVESTIGATOR REQUIREMENTS 
Sponsors are responsible for selecting qualified investigators, providing them 
with the information they need to conduct an investigation properly, ensuring 
proper monitoring of the investigation(s), ensuring that the investigation(s) is 
conducted in accordance with the general investigational plan and protocols 
contained in the IND, maintaining an effective IND with respect to the  
investigations, and ensuring that FDA and all participating investigators are 
promptly informed of significant new adverse effects or risks with respect to 
the drug. 
6.1 
STUDY INITIATION 
Before the start of this study and the shipment of investigational agent to the 
main site and any sub-site, the following documents must be on file at 
Genentech, Inc. 
• Current curricula vitae and license of the Principal Investigator 
• Final Protocol and ICF 
• A signed and dated investigator brochure acceptance form 
• Written documentation of IRB approval of protocol and ICF (identified by 
title and date of approval) for each site 
• A signed Confidentiality Agreement  
• A signed Clinical Trial Agreement for each site  
• A letter of cross-reference to the OSI Pharmaceuticals IND 
 
 
6.2 
STUDY COMPLETION 
The following data and materials are required by Genentech before a study 
can be considered complete or terminated: 
• Copies of protocol amendments and IRB approval/notification, if 
appropriate 
• Copies of the IRB final report, documentation of submission to the IRB 
and to the FDA. 
• A summary of the study prepared by the Principal Investigator (Study 
report, manuscript and/or abstract) 
• All regulatory documents (e.g., updated curriculum vitae for each Principal 
Investigator, updated U.S. FDA Form 1572 for each site) 
 


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37 
6.3 
INFORMED CONSENT 
The informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in 
the study.  The case history for each patient shall document that informed 
consent was obtained prior to participation in the study.  A copy of the 
informed consent documents must be provided to the patient or the patient’s 
legally authorized representative.  If applicable, they will be provided in a 
certified translation of the local language. 
Original signed consent forms must be filed in the site study binder or in each 
patient’s study file. 
 
6.4 
INSTITUTIONAL REVIEW BOARD APPROVAL 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the IRB for review and must be approved 
before the study is initiated.  In addition, any advertising materials must be 
approved by the IRB.  The study will be conducted in accordance with U.S. 
FDA, applicable national and local health authority, and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case the IRB must be updated at least once a year.  
The Principal Investigator must also keep the IRB informed of any significant 
adverse events. 
Investigators are required to promptly notify their respective IRB of all adverse 
drug reactions that are both serious and unexpected.  This generally refers to 
serious adverse events that are not already identified in the Investigator 
Brochure and that are considered possibly or probably related to the study 
drug by the investigator.  Some IRBs may have other specific adverse event 
requirements to which investigators are expected to adhere.  Investigators 
must immediately forward to their IRB any written safety report or update 
provided by Genentech (e.g., IND safety report, Investigator Brochure, safety 
amendments and updates, etc.). 
 
6.5 
STUDY MONITORING REQUIREMENTS 
An important part of routine clinical trial management is scheduled reporting.  
All trials must have and annual review every 365 days per CFR312.33.  The 
Office of Protocol Research will send a reminder notice 60 days prior to the 
anniversary of the last review.  The assigned research team must be able to 
report all protocol related deaths, routine AEs, SAEs. 
Monitoring, accrual, eligibility evaluability, deviations, violations 


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38 
Protocol specific checklists will be developed for the eligibility and protocol 
compliance review.  The following will be audited from both source and 
database entry: 
a. Informed consent 
b. Eligibility/Evaluability 
c. Stratum or randomization 
d. Trial Management or Treatment (correct dose/schedule/therapy) 
e. Scheduled assessments such as labwork and diagnostic tests 
f. Toxicities/adverse events (AEs)/serious adverse events (SAEs) 
g. Response if appropriate, stopping rules or safety assessments as 
written 
h. Off study evaluation 
i. Data verification against source 
 
Department Audit and Monitoring 
Each protocol not already monitored by a sponsor or the ORERM will be a 
priority for Departmental monitoring or audit.  The cases for audit will be 
chosen by reviewing the overall accrual.  A minimum of 10% patient accrual 
will be assessed.  The long term goal of the program is to audit 25% of patient 
accrual.   
 
Once the patients are chosen we will audit a minimum of 1 course of therapy. 
The goal is to audit 30% of the protocol assessment points but the minimum 
will be 10%, or registration date in comparison to treatment date, consent 
form, eligibility criteria, and a full cycle of therapy. 
 
6.6 
DATA COLLECTION 
Data collection for this trial will meet the required elements noted within the 
trial.  
 
6.7 
STUDY MEDICATION ACCOUNTABILITY 
All study drug required for completion of this study will be provided by OSI-
Pharmaceutical (manufacturer), in partnership with Genentech (unless 
otherwise noted).  The recipient will acknowledge receipt of the drug by 


Protocol 2007-0704 
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39 
returning the drug receipt form indicating shipment content and condition.  
Damaged supplies will be replaced. 
Study drug accountability records should be maintained by the site in 
accordance with the regulations. 
The original drug supply request of Tarceva™ will be submitted to Genentech 
along with the form “Approval for Drug Re-Supply”, indicating which personnel 
will be able to submit drug re-supply requests. 
All subsequent drug re-supply requests will be directly submitted to OSI-
Pharmaceuticals from the site. 
At the time of study closure, the unused, used and expired study drug will be 
destroyed at the site per Institutional SOPs and OSI should be provided with 
documentation when this has occurred. 
 
 
6.8 
DISCLOSURE OF DATA 
Patient medical information obtained by this study is confidential, and 
disclosure to third parties other than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his 
or her welfare.  This medical information must be made available to 
Genentech and authorized representatives of Genentech, upon request, for 
source verification of study documentation.   
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, local health authorities, Genentech, Inc, OSI 
Pharmaceuticals and their authorized representative(s), collaborators and 
licensees, and the IRB for each study site, if appropriate. 
 
6.9 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and 
documents pertaining to the conduct of this study and the distribution of 
investigational drug, including CRFs, consent forms, laboratory test results, 
and medication inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval.  If no application 
is filed, these records must be kept 2 years after the study is discontinued and 
the U.S. FDA and the applicable national and local health authorities are 
notified.   


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7. 
REFERENCES 
1. Cerny T, Barnes DM, Hasleton P, Barber PV, Healy K, Gullick W, et al. 
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2. Davies DE, Chamberlin SG. Targeting the epidermal growth factor 
receptor for therapy of carcinomas. Biochem Pharmacol 
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3. DeVita VT, Hellman S, Rosenberg SA, editors. Cancer:  principles and 
practice of oncology. 6th ed. Philadelphia, PA: Lippincott Williams and 
Wilkins; 2001. 
4. Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi H, Angeletti CA, et al. 
Epidermal growth factor receptor (EGFr) expression in non–small cell 
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5. Fossella F. Docetaxel in second-line treatment of non-small-cell lung 
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comparison of epidermal growth factor receptor levels and other 
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7. Gatzemeier U., Pluzanska A., Szczesna A., Kaukel E., Roubec J., 
Brennscheidt U., De Rosa F., Mueller B., Von Pawel J.. TALENT: 
Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin 
and gemcitabine (GC) chemotherapy in advanced non-small cell lung 
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8. Herbst R. S., Prager D., Hermann R., Miller V., Fehrenbacher L., 
Hoffman P., Johnson B., Sandler A. B., Mass R., Johnson D. H. 
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9. IMPATH Inc. Analysis of EGFr Expression in a selection of tumour 
types. IMPATH Study Number PFZ04. 1998-1999:1–16. 
10. Jamal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer 
statistics. CA Cancer J Clin 2003;53:5–26. 


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11. Lei W, Mayotte JE, Levitt ML. Enhancement of chemosensitivity and 
programmed cell death by tyrosine kinase inhibitors correlates with 
EGFR expression in non-small cell lung cancer cells. Anticancer Res 
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12. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, 
Brannigan BW, et al. Activating Mutations in the Epidermal Growth 
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cancer to gefitinib. N Engl J Med 2004;350:1838–49. 
13. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. 
EGFR mutations in lung cancer:  correlations with clinical response to 
gefitinib therapy. Published 29 April 2004. 
http://www.sciencemag.org/cgi/rapidpdf/1099314v1.pdf (accessed 17 
May 2004). 
14. Pfeiffer P, Clausen PP, Andersen K, Rose C. Lack of prognostic 
significance of epidermal growth factor receptor and the oncoprotein 
p185HER-2 in patients with systemically untreated non-small-cell lung 
cancer: an immunohistochemical study on cryosections. Br J Cancer 
1996;74:86–91. 
15. Miller VA, Kris MG, Shah N, Patel J, Azzoli C, Gomez J, et al. 
Bronchioloalveolar pathologic subtype and smoking history predict 
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16. Reissmann PT, Koga H, Figlin RA, Holmes EC, Slamon DJ. 
Amplification and overexpression of the cyclin D1 and epidermal 
growth factor receptor genes in non–small-cell lung cancer. Lung 
Cancer Study Group. J Cancer Res Clin Oncol 1999;125:61–70. 
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Dmitrovsky E. Overexpression of the epidermal growth factor receptor 
and its ligand transforming growth factor alpha is frequent in resectable 
non–small cell lung cancer but does not predict tumor progression. Clin 
Cancer Res 1997;3: 
515–22. 
18. Rusch V, Mendelsohn J, Dmitrovsky E. The epidermal growth factor 
receptor and its ligands as therapeutic targets in human tumors. 
Cytokine Growth Factor Rev 1996;7:133–41. 
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20. Sekine I, Takami S, Guang SG, Yokose T, Kodama T, Nishiwaki Y, et 
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point mutation and c-myc amplification in the carcinogenesis of non-
small cell lung cancer. Oncol Rep 1998;5:351–4. 
21. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, 
et al. Prospective randomized trial of docetaxel versus best supportive 
care in patients with non-small-cell lung cancer previously treated with 
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22. Shepherd FA, Pereira J, Ciuleanu TE, Tan EH, Hirsh V, Thongprasert 
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placebo-controlled trial of erlotinib in patients with advanced non-small 
cell lung cancer (NSCLC) following failure of 1st line or 2nd line 
chemotherapy. A National Cancer Institute of Canada Clinical Trials 
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23. Veale D, Kerr N, Gibson GJ, Kelly PJ, Harris AL. The relationship of 
quantitative epidermal growth factor receptor expression in non-small 
cell lung cancer to long term survival. Br J Cancer 1993;68:162–5. 
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1987;55:513–6. 
 


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APPENDIX A 
Study Flowchart 
 
Assessment 
Screening/ 
baseline 
Weekly    
(± 3 days) 
At 
cystectomy 
 
Follow-up
Informed Consent 
X 
 
 
 
Medical history 
Xa 
 
 
X 
Physical examination 
X 
 
 
X 
Vital signs 
X 
X 
 
X 
Performance status 
X 
 
 
X 
BSA 
X 
 
 
 
Tumor staging 
X 
 
 
X 
CBC with differential and 
platelets 
X 
X 
 
X 
Serum Chemistries 
Xb 
Xc 
 
 
Chest x-ray, CT or MRI of 
abdomen and pelvis, and 
EUA 
Xd 
 
 
X 
Bone Scan 
Xe 
 
 
 
EKG (within 6 months) 
X 
 
 
 
Pregnancy test 
X 
 
 
 
Toxicity 
 
X 
 
X 
Tumor specimen for 
research 
X 
 
X 
 
Blood and urine specimens 
for research 
X 
X 
X 
X 
Cystectomy 
 
 
X 
 
a  Tobacco/smoking history, and exposure to chemicals 
b Electrolytes, BUN, serum creatinine, total bilirubin, alkaline phosphatase, AST or 
ALT, Ca, albumin, LDH 
c Only serum creatinine, AST or ALT and electrolytes. 
d   CXR, CT or MRI, and EUA will be done within 6 weeks of study entry.  (EUA 
only done in the setting of urothelial tumors of the bladder, and will not be 
repeated routinely during follow-up). 
e  Only if alkaline phosphatase > 1.5 X ULN 
 


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APPENDIX B 
List of CYP3A4 Inhibitors 
From http://www.georgetown.edu/departments/pharmacology/davetab.html 
 
The following are known inhibitors of CYP3A4: 
Delaviridine 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir  
Amiodarone  
Cimetidine  
Ciprofloxacin  
Clarithromycin  
Diethyl-dithiocarbamate  
Diltiazem  
Erythromycin  
Fluconazole  
Fluvoxamine  
Gestodene ++  
Grapefruit juice  
Itraconazole  
Ketoconazole  
Mifepristone  
Nefazodone  
Norfloxacin  
Norfluoxetine  
Mibefradil  
Troleandomycin 
Atazanavir 
Indinavir 
Telithromycin 
Voriconazole 
 
The following are known inducers of CYP3A4: 
Rifampicin 
Phenytoin 
Rifabutin 
Rifapentine 
Carbamazepine 
Phenobarbital 
St. John’s Wort 
 
 
 
APPENDIX C 
ECOG Performance Status Scale 
 
 


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45 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about >50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair 
>50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.   
Totally confined to bed or chair 
5 
Dead