Clinical trial NCT00402779
Conditions: Oral Cancer
Keywords: Oral Cancer Oral IEN Lesion with LOH Loss of Heterozygosity Intraepithelial Neoplasia Placebo Erlotinib Tarceva OSI-774
Sponsor: M.D. Anderson Cancer Center
Start date: 2006-11-03; Completion date: 2018-06-04
Enrollment: 303 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if erlotinib hydrochloride (Tarcevaâ (OSI-774 ) can prevent cancer in the mouth of people with a high risk of developing cancer in the mouth. The safety of this drug will also be studied, as well as the drug's effect on different cells in the body.

Detailed description:
Erlotinib hydrochloride is designed to block the activity of an enzyme found on the surface of many tumor cells that may control tumor growth and survival. This may keep tumors from growing.

If you are found to be eligible to participate in the study, you will be randomly assigned (as in the toss of a coin) to receive either erlotinib hydrochloride or placebo. A placebo is a substance that looks like the study drug but has no active ingredients. Neither you nor the investigators will know which treatment group you have been assigned to. However, in the event of a medical emergency, the study chair can find out which group you are in, if necessary. You can be informed which of the groups you were assigned to, after the study has ended. There is no certainty that you will have an effect from the treatment, or if you will be placed in a group with the active study drug.

While on study, you will take the study dose (either erlotinib hydrochloride or placebo) by mouth, in tablet form, once a day. Tablets should be taken in the morning 1 hour before or 2 hours after a meal, other medications, vitamins, and iron supplements, with no more than 7 ounces of water. You should take the study dose around the same time every day. Every attempt should be made to keep from vomiting the dose, for at least 30 minutes after taking it. For example, if you feel nauseated before or after taking the study dose, anti-nausea medications should be used. If you vomit after taking the study dose, the dose can be taken again only if the tablet(s) can actually be seen and counted (in other words, they have not dissolved yet). You will need to note the time you take each dose of medication throughout the study on a calendar that the study nurse will give to you.

At Months 1, 3, 6, 9, and 12, you will return to clinic. You will have a physical exam including measurement of vital signs. You will have a careful examination of the inside of your mouth.You will have blood (about 2 teaspoons) drawn for routine tests and to check your liver function (about 1-2 teaspoons). At Months 3, 6, and 12, you will have blood (about 2 teaspoons) drawn for research testing and to measure the level of study drug in the body.

Your study doctor will ask you about any medications you are taking, how you are feeling (symptoms), and your current smoking and alcohol usage.

The nurse or study coordinator will collect the medication you did not take, as well as your completed pill diaries, at every clinic visit. At Months 1, 3, 6, and 9, you will also be given new study medication and pill diaries.

You may also have another small biopsy performed from the inside of your mouth in the area where the cells that might become cancerous are located. The biopsy will be performed by your doctor and will be sent to a lab for testing. At months 3 and 12, the doctor will also count and measure any red or white patches on the inside of your mouth. Biopsies will be taken after 3 months of treatment and at the end of 12 months of treatment. The tissue will be tested to see if there are any cells that might become cancerous.

Following the end of treatment, you will return to the clinic every 6 months for 2 years. You will have a complete physical exam, including measurement of vital signs. You will have a careful examination of the inside of your mouth. You will have blood drawn (about 2 teaspoons) for routine tests, to check your liver function, and for research testing. Your study doctor will ask you about any medications you are taking and how you are feeling (symptoms), and your current tobacco and alcohol use.

In addition, at the final clinic visit, you will also take part in a personal interview. During the interview, you will be asked questions regarding socio-demographic information (such as age and race), nutrition habits, current and earlier tobacco use, alcohol use habits, family history of cancer, use of medications, and how you are feeling. The interview will take about 90 minutes to complete. The purpose of the interview is to collect information to learn if there is a relationship between certain factors and your risk of developing cancer of the mouth. You may be contacted in the future in order to collect more information.

You may be taken off study if you are not able to follow the doctors' instructions, serious side effects occur, or the doctor thinks it is in your best interest to leave the study. If you are taken off study for any reason, you will be asked to return to the clinic for a final clinic visit, preferably within 14 days after leaving the study.

This is an investigational study. Erlotinib hydrochloride is approved by the FDA for treatment of NSCLC. Its use in this study is considered investigational. Approximately 491 patients will be screened for this study. Up to 120 will be enrolled at MD Anderson.

Arms: arm 1: Balanced randomization: Erlotinib 150 mg continuous administration for 1 year. arm 2: Balanced randomization: Placebo continuous administration for 1 year.
Interventions: intervention 1: Erlotinib intervention 2: Placebo
Intervention descriptions: intervention 1: 150 mg by mouth daily intervention 2: Tablet by mouth daily

Protocol documents:
Prot_SAP_000.pdf: 
MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 1 
 
 
 
 
 
 
MDACC SPONSOR VERSION #8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL  
Erlotinib Prevention of Oral Cancer (EPOC) 






MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 4 
 
SCHEMA 
 
Erlotinib Prevention of Oral Cancer (EPOC) 
 
 
Males and females > 18 years of age with a confirmed diagnosis of oral leukoplakia and LOH or 
confirmed diagnosis of oral leukoplakia, LOH and prior oral cancer (cured) 
 
Pre-study/ Baseline 
Informed consent, smoking status and alcohol usage, epidemiological and nutrition questionnaire, family 
history of cancer, medical history, physical examination including vital signs and performance status, 
examination of the oral cavity (including baseline quantitation and bidimensional measurements of visible 
lesions), hematology, chemistry, -HCG in women of childbearing potential, blood for biomarker assays, 
isolation of lymphocytes, plasma trough levels, concomitant medication review. Archival diagnostic tissue 
sample(s) or biopsy of oral leukoplakia lesions for LOH (Loss of Heterozygosity) status 
 
Eligible patients with oral leukoplakia and LOH +/- prior oral cancer (cured) 
 
Randomization 
Balanced randomization to one of two arms:  Erlotinib (150 mg po QD) or placebo continuous 
administration for 1 year  
 
Months 1 thru 3: 
Clinic visits at months 1 and 3: Full physical examination including vital signs, smoking status and alcohol 
usage, examination of the oral cavity, hematology, chemistry, blood for biomarker assays and plasma 
trough levels (at month 3), concomitant medication review, adverse event and symptom assessment, 
return of completed pill diaries and unused medication returned, new medication and pill diaries 
dispensed at months 1 and 3.  For patients with visible oral leukoplakia lesions, quantitation of lesions, 
bidimensional measurements, and biopsy will be obtained at month 3. For patients with no visible oral 
leukoplakia lesions, a biopsy will be obtained at the site of the previous lesion biopsy or at mucosa 
adjacent to cancer resection at month 3. 
 
Months 4 thru 11 
Clinic visits at months 6 and 9: Full physical examination including vital signs, smoking status and alcohol 
usage, examination of the oral cavity, hematology, chemistry, blood for biomarker assays and plasma 
trough levels (at month 6), concomitant medication review, adverse event and symptom assessment, 
return of completed pill diaries and unused medication returned, new medication and pill diaries 
dispensed 
 
Month 12 or Early Termination 
Clinic visit: Full physical examination including vital signs, smoking status and alcohol usage, examination 
of the oral cavity, hematology, chemistry, blood for biomarker assays and plasma trough levels, 
concomitant medication review, adverse event and symptom assessment, return of completed pill diaries 
and unused medication returned. For patients with visible oral leukoplakia lesions, quantitation of lesions, 
bidimensional measurements, and biopsy will be obtained. For patients with no visible oral leukoplakia 
lesions, a biopsy will be obtained at the site of the previous lesion biopsy or at mucosa adjacent to cancer 
resection. 
 
Follow-Up Clinic Visits Every Six Months  
Clinic Visit: Full physical examination including vital signs, smoking status and alcohol usage, 
examination of the oral cavity, hematology, chemistry, blood for biomarker assays, symptom assessment 
and epidemiological and nutrition questionnaire (at final visit only) 
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 5  
 
 
 
TABLE OF CONTENTS 
 
Page 
COVER PAGE ..................................................................................................................................... 1 
SCHEMA .............................................................................................................................................. 4 
 
1. OBJECTIVES ................................................................................................................................ 7 
1.1 
Primary Aim ....................................................................................................................... 7  
1.2 
Secondary Aims ................................................................................................................ 7 
 
2. BACKGROUND ............................................................................................................................. 8 
2.1 
Study Disease-Oral Carcinogenesis .................................................................................. 8 
2.2 
EGFR Inhibition ............................................................................................................... 11 
2.3 
Study Agent..................................................................................................................... 12 
 
3. SUMMARY OF STUDY PLAN ..................................................................................................... 14 
 
4. PARTICIPANT SELECTION ........................................................................................................ 15 
4.1 
Inclusion Criteria ............................................................................................................. 15 
4.2 
Exclusion Criteria ............................................................................................................ 16 
4.3 
Inclusion of Women and Minorities ................................................................................. 16 
4.4 
Recruitment and Retention Plan  .................................................................................... 16 
 
5. AGENT ADMINISTRATION 
5.1 
Dose Regimen and Dose Groups .................................................................................... 19 
5.2 
Rationale for Dose Selection ........................................................................................ ....19 
5.3 
Study Agent Administration ............................................................................................. 20 
5.4 
Concomitant Medications ................................................................................................ 20 
5.5 
Compliance  .................................................................................................................... 20 
 
6. PHARMACEUTICAL INFORMATION ......................................................................................... 20 
6.1 
Study Agent-Erlotinib  ..................................................................................................... 20 
6.2 
Reported Adverse Events and Potential Risks ................................................................ 21 
6.3 
Availability and Accountability ......................................................................................... 22 
6.4 
Dispensing ...................................................................................................................... 22 
6.5 
Randomization and Blinding ........................................................................................... 22 
 
7. CLINICAL EVALUATIONS AND PROCEDURES ....................................................................... 24 
7.1        Schedule of Events  ........................................................................................................ 24 
7.2 
 Baseline Testing/Pre-study Evaluation ............................................................................ 25 
7.3 
 Randomization ................................................................................................................ 26 
7.4 
 On-Study Evaluations (Active Treatment Period) ............................................................ 26 
7.5 
 Follow-up ........................................................................................................................ 27 
7.6 
 Long-term Follow-up ....................................................................................................... 27 
7.7 
Methods for Clinical Procedures ....................................................................................... 27 
 
8. CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION .................................................. 29 
8.1 
Primary Endpoint ............................................................................................................ 30 
8.2 
Planned Secondary Endpoints and Analytical Methods .................................................. 30 
8.3 
Off Agent Criteria ............................................................................................................ 31 
8.4 
Off Study Criteria ............................................................................................................ 32 
8.5 
Study Termination ........................................................................................................... 32 
9. REPORTING ADVERSE EVENTS .............................................................................................. 32 
9.1 
Adverse Events ............................................................................................................... 32 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 6 
 
9.2 
Serious Adverse Events .................................................................................................. 33 
 
10. MANAGING ADVERSE EVENTS/TOXICITIES/EARLY TERMINATIONS .................................. 34 
10.1 
Adverse Events  .............................................................................................................. 34 
10.2 
Causal Relationship of AE to Study Medication............................................................... 35 
10.3 
Toxicity Attribution and Dose Reduction .......................................................................... 35 
 
11. STUDY MONITORING ................................................................................................................. 37 
 
12. STATISTICAL CONSIDERATIONS ............................................................................................ 38 
12.1 
Study Design/Endpoints .................................................................................................. 38 
12.2 
Analysis of Primary Endpoint .......................................................................................... 38 
 
13. ETHICAL AND REGULATORY CONSIDERATIONS .................................................................. 39 
13.1 
Ethical Standards and Notifications ................................................................................. 39 
13.2 
IRB Approval ................................................................................................................... 39 
13.3 
Patient Data Protection and Confidentiality ..................................................................... 40 
13.4 
Informed Consent ............................................................................................................ 40 
 
14. FINANCIAL SUPPORT AND DISCLOSURE ............................................................................... 41 
14.1 
Financial Support ............................................................................................................ 41 
14.2 
Financial Disclosure ........................................................................................................ 41 
 
REFERENCES  ........................................................................................................................... 42 
 
APPENDICES 
 Appendix A. 
Epidemiological and Nutrition Questionnaires 
 
 
 Appendix B. 
Eastern  Cooperative Oncology Group (ECOG) Performance Status   
Criteria  
 
Appendix C. 
Charter for the Data and Safety Monitoring Board of the Oral Leukoplakia  
Study 
 
Appendix D.  
Partial List of Drugs That May Affect the Metabolism of Erlotinib  
(Tarceva) 
 
Appendix E.   
Common Toxicity Criteria for Adverse Events v3.0 (CTCAE) 
 
Appendix F.    
Guidelines for Filing Reports of Adverse Experiences at M. D. Anderson 
Cancer Center 
 
Appendix  G.  
Sample Preparation and Shipment Guidelines: Memorial Sloan Kettering 
Cancer Center, Emory University, University of Chicago, and University 
of Maryland 
 
Appendix  H.  
Prioritization List 
 
Appendix  I.  
Protocol Checklist 
 
 
 
 
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 7 
 
 
 
1. 
OBJECTIVES 
This study will test the ability of an epidermal growth factor receptor (EGFR) inhibitor 
(erlotinib) to reduce the incidence of oral cancer in the high-risk setting of oral 
leukoplakia with LOH in two cohorts, oral IEN (Intraepithelial neoplasia) patients with 
LOH in 3p and/or 9p and one other specific chromosomal locus but without cancer or 
oral IEN patients with LOH in 3p and/or 9p associated with curatively treated oral cancer.  
We will test this treatment in a randomized clinical trial with 2 treatment arms: Erlotinib 
150mg po QD or placebo. 
 
1.1 
Primary Aim 
The primary endpoint of the trial will be the oral cancer-free survival in patients 
receiving erlotinib as compared with the control or placebo group.  
 
1.2 
Secondary Aims 
 
1.2.1  The size, number, and appearance of oral IEN will be assessed and 
correlated with cancer risk. A > 50% reduction in the bidimensional 
measurements of IEN lesions is considered a treatment response. We 
hypothesize that patients with IEN lesions and LOH of the oral cavity will 
respond to erlotinib. 
1.2.2 To examine toxicity associated with erlotinib. Our hypothesis is that 
patients with oral lesions will tolerate treatment with erlotinib. 
1.2.3 To assess a panel of molecular markers for correlations with oral cancer 
development in our oral IEN patients. The markers will include (but are 
not restricted to): 
 
1.2.3.1 
EGFR, 
phospho-EGFR, 
TGF-alpha, 
ERK1/2, 
phospho-
ERK1/2, AKT, phospho-AKT, COX-2, STAT3, phospho-
STAT3, cyclin D1, HER2, Ki67, TUNEL, RAR-beta, hTERT 
expression, E-cadherin, P-cadherin, vimentin, Src, phospho-
Src, cytokeratin 
1.2.3.2 
EGFR gene copy number 
1.2.3.3 
PGE2 levels 
1.2.3.4 
DNA ploidy analysis 
1.2.3.5 
Promoter methylation on p16 and in FHIT 
1.2.3.6 
Protein profiling in serum 
1.2.3.7 
Chromosome–9-related levels of polysomy, chromosome 
index and fraction of cells involved in subclonal outgrowth 
1.2.3.8 
BPDE-induced genetic damage 
1.2.3.9 
Frequency of polymorphisms in the following DNA-repair 
genes implicated in the nucleotide excision repair (NER) 
pathway: ERCC1, XPC, XPD/ERCC2, EXPF/ERC4, XPA, 
RAD23B, CLNH, ERCC5, LIG1.   
1.2.3.10 
Frequencies of BPDE chromosomal aberrations on 3p12.3, 
3p14.2, 3p21.3 and 3p25.2.  
1.2.3.11 
Polymorphisms of CYP1A1, CYP3A4, CCND1, COX-2, EGFR,   
and ErbB-2. 
1.2.3.12 
Genome wide single nucleotide polymorphisms, telomere 
length, mitochondrial DNA alterations 
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 8 
 
 
2. 
BACKGROUND 
 
2.1 
Study Disease—Oral Carcinogenesis 
Oral squamous cell carcinoma (OSCC) is a disfiguring, aggressive epithelial malignancy 
associated with high mortality and severe morbidity in long-term survivors. More than 
300,000 annual new cases are diagnosed worldwide. Treating oral leukoplakia, the most 
common oral IEN and a precursor lesion of oral cancer, varies from watchful waiting to 
complete resection.1,2  The prevalence rate of oral IEN ranges from 2%-8% in older 
persons.3  Oral cancer incidence is increasing, and oropharyngeal cancer is the sixth 
most common cancer in adults in western countries. Almost 50% of the patients in the 
oncology departments of some developing countries suffer from oral cancer. Despite 
recent advances in screening and treatment, the long-term survival of patients with 
OSCC has only marginally improved over the past three decades, only 50% of OSCC 
patients survive 5 years after diagnosis.1-4 
 
Etiology 
Epidemiologic data established tobacco and alcohol use as the major causes of oral 
cancer.4-7  Oral cancer risk is almost 10 times greater in individuals who do than who do 
not smoke and drink and almost 100 times greater in persons who smoke and drink 
heavily.  A substantial percentage of the people with these risk behaviors, however, do 
not develop cancer. Other OSCC risk factors are betel quid chewing and possibly 
marijuana use.8  These factors, and tobacco and alcohol use, also increase the risk of 
oral IEN.9  The risk of oral cancer with any type of unfiltered cigarette is twice that of 
filtered cigarettes,6 and the risk associated with hand-rolled unfiltered cigarettes is higher 
than that of factory-made unfiltered cigarettes.10 
 
Although human papilloma virus (HPV) infection has been hypothesized for decades to 
play a role in the etiology of oral neoplasia, various studies have found different and 
contradictory frequencies of HPV DNA detection in oral mucosal lesions.11,12  Recent 
data from the largest sample size yet analyzed could not establish a link between HPV 
infection and the development of either regular or more-aggressive verrucous oral IEN.13  
Nevertheless, HPV may be involved in some patients who develop oral neoplasia, for 
example, in a subset of OSCC patients without tobacco or alcohol risk factors. 
 
Multifocal, Multistep Carcinogenesis 
Oral cancer development is a multifocal process due both to multiclonal development 
and clonal intraepithelial spread.2,4,14-16  Multifocality likely is a major cause of the failure 
of local treatment of oral IEN in preventing oral cancer and supports the testing of 
systemic therapy with agents targeting signaling pathways relevant to oral 
carcinogenesis such as the EGFR pathways.  
 
Head and neck carcinogenesis is a multistep process requiring the accumulation of 
multiple genetic alterations.1,4,17-27  Extensive genetic analysis of oral cancers and oral 
IEN has identified many common genetic abnormalities.  LOH, a result of genetic 
instability and clonal selection, is one of the major mechanisms to inactivate tumor 
suppressor genes.  Our earlier study showed that IEN with LOH at 3p14 and/or 9p21 
regions increases the IEN risk for developing invasive oral cancer.19  The 3-year oral 
cancer incidence in the LOH group was approximately 25%.  The region 3p14 contains 
the tumor suppressor gene FHIT, and 9p21 contains the tumor suppressor genes 
p16/p15/p14, supporting the hypothesis that clones with deletions at these chromosomal 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 9 
 
regions are more advanced in the tumorigenic process.  Several subsequent studies by 
other groups had similar results and conclusions.20,21,23-26 
 
Rosin et al. employed their centralized Oral Biopsy Service and the database of the 
British Columbia Cancer Registry to identify 116 patients who had oral IEN and who had 
been followed for a long period.23  Importantly, only patients whose oral lesions had 
moderate histological changes (hyperplasia or mild or moderate dysplasia) similar to our 
earlier study19 were selected for the study.  The 3-year oral cancer incidence in the 3p14 
and/or 9p21 LOH group was remarkably similar (25%) to our earlier study.  A substantial 
proportion of lesions with LOH at 3p14 and/or 9p21 did not develop oral cancer, and so 
this group investigated the additional chromosomal loci 4q, 8p, 11q, 13q, and 17p, which 
are commonly deleted in oral cancers.23  They found that LOH at one of these additional 
loci plus at 3p14 and/or 9p21 significantly improved the ability of LOH to predict oral 
cancer development.  The 3-year cancer rate was 35%, and this expanded LOH profile 
was found in approximately 28% of the oral lesions.  Several tumor suppressor or 
candidate tumor suppressor genes, such as TRAIL-R1 and TRAIL-R2 at 8p21.3 and p53 
tumor suppressor gene at 17p13, are located in these chromosomal regions. 
 
Rosin et al. also have retrospectively studied the oral cancer risk of LOH in IEN of 
patients with a history of curatively treated oral cancer.27  LOH at 3p14 and/or 9p21 in 
IEN associated with curatively treated oral cancer has a 69% risk of a subsequent oral 
cancer in 3 years, and the prevalence of this LOH was approximately 66% among these 
cancer survivors with IEN.  In order to confirm these retrospective data, this research 
group developed a prospective study in the same setting (R01 DE13124, “Clonal 
Changes in Oral Lesions of High-Risk Patients”).  The preliminary results indicate that 
the rate of LOH on 3p and/or 9p in IEN and the rate of oral cancer are similar between 
the ongoing prospective and earlier retrospective studies in these curatively treated 
cancer patients (Personal communication, M. Rosin, Feb. 2006).  LOH is a powerful, 
feasible risk marker that has been confirmed by multiple research groups and allows for 
selecting patients at M. D. Anderson Cancer Center and three other U.S. cancer centers 
for a phase III prevention trial.   
 
High-risk oral IEN and early-stage oral cancer have overlapping molecular targets for 
intervention agents such as erlotinib.  It can be very difficult to determine if a new cancer 
is an SPT (second primary tumor) or a recurrence in the setting of definitively treated 
early-stage aerodigestive tract cancer.28-31  In our phase III SPT chemoprevention trial 
(NCI P01 CA52051), we examined patients treated curatively for early-stage head and 
neck cancer and who subsequently developed new cancer that was rigorously 
determined clinically to be either an SPT or recurrence.31  Genetic profiling of the initial 
and subsequent cancers in these patients revealed substantial molecular ambiguity 
regarding the origins of the subsequent cancers.32  For example, over 50% of the 
clinically defined SPTs were molecularly determined to be recurrences (i.e., genetic 
profiles consistent with clonal spread of the original tumor).  We plan to examine 
distinctions between SPTs and recurrence based on patterns and mathematical 
modeling of genetic alterations (LOH, specific mutations of p53, and microsatellite 
instability) within cancers that develop in study patients with a cancer history; this 
approach also will be applied to determining clonal relationships between IEN and 
cancer in patients with or without a cancer history.  Nevertheless, whether preventing 
SPT or recurrence, we believe that our trial has a high potential to bring clinical benefit to 
patients with a critical medical need through an approach that addresses the interfacing 
challenges presented by cancer prevention and therapy.33,34 
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 10 
 
 
 
Systemic Retinoid Approaches 
Retinoids are the most-studied cancer preventive agent in oral carcinogenesis, and our 
collaborative group developed one of the largest programs of retinoid research in this 
setting in the world. Although largely predating molecular-targeted approaches, the oral 
IEN model produced seminal clinical and laboratory advances in our understanding of 
oral carcinogenesis and its response to retinoids, in particular, and of molecular targets 
for cancer prevention (and therapy) in general. The decades-long history of clinical 
retinoid trials includes five early randomized trials in oral IEN, one of which presaged 
another retinoid trial involving second primary tumor (SPT) prevention in head and neck 
cancer 
patients 
that 
provided 
a 
proof 
of 
principle 
for 
human 
cancer 
chemoprevention.29,35-38 We showed that a high-dose of the retinoid 13-cis-retinoic acid 
(13cRA) can reverse oral IEN in the short term and reduce the SPT risk of definitively 
resected head and neck cancer patients. However, toxicity was substantial and not 
acceptable for long-term prevention and activity was reversible with high-dose 
13cRA.29,37-39 These high-dose, short-term results led to a randomized maintenance trial 
in oral IEN designed to reduce the toxicity of and prolong the response to a 3-month 
induction course of high-dose 13cRA (1.5 mg/kg/d) via a 9-month maintenance course 
with low-dose 13cRA (0.5 mg/kg/d) or beta-carotene (30 mg/d) in responding or stable 
oral IEN patients of the induction phase.40 The maintenance-phase clinical lesion 
progression rates were significantly lower in the retinoid group than in the beta-carotene 
group. Therefore, we tested low-dose 13cRA (versus placebo) in a long-term, large-
scale, NCI Intergroup phase III trial to prevent SPTs in early-stage head and neck 
cancer patients. This trial found no significant difference in SPT rates between the 
13cRA and placebo arms.31 Studies of retinoid-interferon combinations in advanced oral 
and laryngeal IEN have produced promising results in advanced laryngeal but only 
limited activity in advanced oral IEN.41 
 
Translational studies in the retinoid–oral IEN model have helped to advance the overall 
understanding of the biology of intraepithelial carcinogenesis, preventive agent 
molecular targets and mechanisms, and markers for developing drugs, monitoring 
interventions, and assessing cancer risk and pharmacogenomics. These studies have 
assessed retinoic acid receptor-beta (RAR-), p53, p16 genetic instability, LOH, and 
cyclin D1, among other markers of tumorigenesis and/or risk38.  Extensive studies of 
nuclear RARs in the retinoid-oral IEN model include a study by Lotan et al42 that found a 
selective and progressive loss of RAR- (one of six RARs) in oral carcinogenesis, a 
striking upregulation of RAR- expression after 3 months of high-dose 13cRA, and a 
significant association of RAR- upregulation with clinical IEN response. RAR- loss was 
associated with immortalization in short-term in vitro cultures of oral IEN cells.43  Recent 
studies indicate potential mechanisms of RAR- loss, including a defect in intracellular 
RA metabolism and RAR- silencing by methylation and histone deacetylation.44,45  
RAR- is expressed in three isoforms in humans (1, 2, and 4). RAR-2, the most 
abundant and inducible form, has tumor suppressor activity. RAR-4 has oncogenic 
activity.  Recent studies also show that the tobacco carcinogen benzo(a)pyrene 
diolepoxide (BPDE) suppresses RAR-2 in vitro and that there is an inverse relationship 
between RAR- and COX-2 in oral cancer cells in vitro and in oral leukoplakia, and that 
RAR-2 transfection suppresses EGFR and COX-2 in vitro.46-48  A recent study 
suggested that the GG genotype of cyclin D1 can mark retinoid sensitivity in patients 
with advanced head and neck IEN to retinoic acid (likely related to effects on ubiquitin-
dependent proteolysis) as indicated by cyclin D1 protein modulation, IEN response, and 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 11 
 
progression free survival.49  The beneficial drug effect in patients with the GG genotype 
was lost shortly after the 1-year intervention was stopped.  Cancer development in 
patients with the GG genotype began approximately 1 year after stopping the 
intervention at an annual cancer rate paralleling that of patients with the retinoid-
resistant AA or AG genotypes.  Studies in advanced oral IEN indicate the importance of 
molecular confirmation with LOH of IEN response.50  Molecular-targeted drug 
development in carcinogenesis of the head and neck or any other region or site has 
benefited enormously from translational research in the retinoid–oral IEN model, which 
has helped pioneer rigorous scientific and clinical methodologies, including reliable 
sampling methods, for clinical and translational studies of oral IEN such as the studies 
governed by this protocol.38 
 
Over the past 10 years, our group and others have conducted molecular studies of 
genetic instability and loss of heterozygosity for identifying head and neck IEN patients 
who have a high risk of oral cancer.19,22-27,38,51  Molecular markers of the varying cancer 
risks of oral IEN have revolutionized drug development in this setting. Substantial 
evidence points to genetic instability as a cause rather than as a consequence of 
malignant transformation.  Mutations in genes controlling chromosome segregation 
during mitosis and centrosome abnormalities play a critical role in the development of 
chromosome instability in cancer.  This high-risk population allows the protocol trial to 
use cancer as the primary endpoint, the value of which is illustrated by our recent, 
unpublished data from the largest retinoid trial ever conducted in oral IEN.  Oral cancer 
development did not correlate with retinoid response in this trial, which was sponsored 
by the NCI and involved lesions with a lower risk than that of IEN with LOH. The present 
protocol trial will assess IEN response (with LOH) in addition to cancer, allowing an 
assessment of the potential correlation between lesion response and cancer outcome.  
In summary, we chose IEN with LOH because it is a powerful known predictor of oral 
cancer development.  
 
2.2 
EGFR Inhibition 
The strong rationale for EGFR inhibition in this setting is based on the following 
constellation of findings:  1) EGFR is overexpressed in virtually all oral IEN;52,53 2) levels 
of EGFR ligands are increased in oral IEN and in the oral mucosa of smokers;53,54 3) 
suppression of EGFR signaling leads to reduced levels of cyclooxygenase-2 (COX-2) 
and decreased synthesis of prostaglandin E2 (PGE2) in a model of oral IEN; PGE2-
mediated activation of EGFR signaling is dampened by an EGFR TKI;55 4) EGFR TKIs 
suppress growth in oral cancer xenografts and IEN cells;54-59 and 5) suppression of 
EGFR signaling is active in preclinical (in vivo) and clinical head and neck and lung 
prevention models.38,60  Two additional strengths of the rationale, i.e., important clinical 
findings and the suppression of levels of cyclin D1 and genetic instability, are discussed 
in detail below. 
 
Our group has found that increased cyclin D1 expression is associated with genetic 
instability and cancer risk in head and neck IEN.49  Consistent with recent data of 
others,61 our recent studies in cultured IEN cells transfected with an inducible cyclin D1 
vector demonstrated that upregulation of cyclin D1 induces genetic instability in a dose-
dependent fashion; decreasing cyclin D1 expression leads to decreased genetic 
instability.  Suppressed cyclin D1 is the only biomarker endpoint of drug efficacy that has 
been shown clinically to correlate with reduced cancer risk in the setting of head and 
neck IEN.  As reviewed earlier, a retinoid-based regimen significantly suppressed cyclin 
D1 and genetic instability and delayed the onset of cancer in advanced head and neck 
IEN patients with the GG genotype of cyclin D1 but not with the AA or AG genotype (A 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 12 
 
allele).49  Laboratory data of Dimitrovsky’s group suggest why the clinical response 
differed by cyclin D1 genotype.  Retinoids decrease cyclin D1 expression through 
ubiquitin-mediated protein degradation.  The A allele, however, produces an alternatively 
spliced RNA transcript that encodes a cyclin D1 form that is resistant to ubiquitin-
mediated protein degradation.62  These results, which provide the proof of principle of 
head and neck cancer prevention via down-regulation of cyclin D1, are extremely 
relevant rationale for the use of EGFR inhibitors such as erlotinib. Because EGFR can 
induce the transcription of cyclin D1 via STAT363,64 and this pathway can be suppressed 
by EGFR inhibitors in head and neck cancer, erlotinib can suppress cyclin D1 
expression at the level of gene transcription, which may broaden its cancer preventive 
effects to patients with any cyclin D1 genotype. 
 
Overexpression of EGFR, STAT3 and cyclin D1 have been shown to be poor prognostic 
factors in head and neck cancer patients.65,66  Limited clinical data show that erlotinib 
(150 mg/day) produced pathologic responses in head and neck/lung cancers that 
correlated with higher concentrations of the drug in tumor tissue and with the 
suppression of cyclin D1.67  EGFR can induce Snail to transcriptionally suppress E-
cadherin, which is associated with the following events:  MMP activation and dysplasia in 
oral IEN and a highly aggressive phenotype, poor response to EGFR TKIs, and poor 
prognosis in head and neck cancer.68-72  In oral IEN cells in vitro, an EGFR TKI 
downregulates extracellular matrix metalloproteinase inducer, which is important for 
tumor invasion and angiogenesis and is overexpressed in oral IEN biopsy specimens.73  
Furthermore, PGE2 also can induce cyclin D1 transcription, either through an EGFR-
dependent (positive feedback loop) or -independent mechanism.73-75  Therefore, erlotinib 
potentially can decrease cyclin D1 levels, in part, by suppressing PGE2 synthesis.  In 
preclinical head and neck IEN and cancer models, the activity of a high-dose single-
agent EGFR inhibitor is similar to that of combined low-dose EGFR and COX-2 
inhibitors.77,78  This equivalency likely is due to the beneficial impact of the high-dose 
EGFR inhibitor on interactions between the COX-2 and EGFR signaling pathways as 
well as on EGFR signaling pathways not known to involve COX-2. 
 
Substantial further clinical support, such as from the following data, also support erlotinib 
(150 mg/day):  patient plasma erlotinib concentrations are equivalent to active 
concentrations in preclinical head and neck/lung cancer models; recent phase III data 
led to the FDA approval of erlotinib for treating two tobacco-related cancers, including 
the approval of single-agent erlotinib for non-small cell lung cancer (NSCLC).79  
Moreover, there are several relevant trials in recurrent/metastatic head and neck cancer 
patients, including single-agent trials of the EGFR inhibitors gefitinib, cetuximab and 
erlotinib, which produced promising safety and efficacy results suggesting a dose-
response relationship,80-82 and a phase II trial showing high activity of a chemotherapy 
combination with an EGFR-inhibitor.83  There also is a phase III trial showing that an 
EGFR inhibitor combined with radiation improved survival over that of radiation alone in 
locally/regionally advance head and neck cancer patients.84,85  An EGFR inhibitor is 
more likely to affect growth in oral IEN than in oral cancer because genetic damage and 
instability have progressed to a lesser degree in IEN than in cancer. 
 
2.3 
Study Agent 
Erlotinib 
One approach to block EGFR activity involves the use of small molecules to inhibit 
tyrosine kinase activity of erbB-1 receptor.86-88 Protein kinases are a family of cellular 
components that regulate signaling for a wide variety of cellular processes such as 
growth and differentiation.  They are divided into subgroups based on the amino acid 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 13 
 
substrate for phosphorylation: serine, threonine or tyrosine. Tyrosine kinase was the last 
to be identified following the discovery of the Rous sarcoma virus src gene 
approximately 20 years ago. Tyrosine kinase activity is considered a hallmark of the 
transformation of malignant cells. Substantial evidence in vivo and in vitro points to the 
close relationship between tyrosine kinase activity and the initiation, growth and 
metastases of many human tumors. 
 
Tyrosine kinase is the intracellular domain of the EGFR and the other members of the 
erbB family except the c-erbB-3. As such, it serves as the first step in the EGF signal 
transduction pathway. The binding of a ligand to the extracellular domain of EGFR 
activates the intrinsic tyrosine kinase activity, which then, transfers the terminal 
phosphate group of adenosine triphosphate to the hydroxyl group of specific tyrosine 
residues of target proteins and of the receptors themselves. Tyrosine kinase has several 
protein substrates, PLC-1, PI-3 kinase, GAP, MAP kinase, raf kinase, and lipocortin I. 
Although growth factors and their receptors vary in structure, tyrosine kinase activity 
remains the initial step in the mechanism of action for all growth factors. The discovery 
of small molecules that interfere with ATP binding or utilization represented a major 
breakthrough in tyrosine kinase-targeted therapy. In the last two decades, enormous 
efforts have been made to develop compounds that can inhibit tyrosine kinase activity 
and several kinase inhibitors have been generated and successfully inhibited cell cycle 
progression and induced apoptosis in both human tumor cell lines in vitro and in 
xenograft models. Inhibitors bind intracellularly to EGFR tyrosine kinase, inhibit kinase 
activity, and subsequently block the signal transduction cascade. Tyrosine kinase 
inhibitors (TKIs) targeting the intracellular domain are small molecules that specifically 
inhibit EGFR tyrosine kinase activity over precise dose ranges. Several different classes 
of TKIs have been reported after molecular modeling has been employed to develop 
compounds that can selectively and tightly bind to various kinase targets. The 
quinazolines and the pyridopyrimidines currently appear to be the most promising 
classes of the TKIs. 
 
Erlotinib (OSI-774, Tarceva) is an orally bioavailable EGFR TKI low-molecular weight 
quinazoline derivative. This novel drug induces cell cycle arrest at the G1 phase and has 
a high specificity as an inhibitor of the EGFR tyrosine kinase. Erlotinib acts through 
direct and reversible inhibition of EGFR tyrosine kinase.89 Erlotinib inhibits 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 inhibition is selective for EGFR tyrosine kinase in assays of isolated 
tyrosine kinases and cellular assays. EGFR is overexpressed in a significant percentage 
of epithelium-derived carcinomas. Erlotinib inhibits the EGF-dependent proliferation of 
cells at nanomolar concentrations and blocks cell cycle progression at the G1 phase. 
Oral administration of erlotinib to mice reduced the level of EGFR autophosphorylation in 
human tumor xenografts by > 70% for more than 12 hours.90 Daily administration of 
erlotinib markedly inhibited the growth of HN5 human head and neck tumors and A431 
squamous cell carcinoma xenografts in aythymic mice, with near complete inhibition of 
tumor growth during a 20-day treatment regimen at the highest doses. Many other 
potential effects of erlotinib in oral cancer prevention and therapy, including the 
abrogation of EGFR-dependent induction of COX-2 are discussed above in Section 2.2. 
Erlotinib also has  been shown to downregulate cyclin D1,67 which is upregulated in head 
and neck IEN and has been reduced by other agents in preventing head and neck 
carcinogenesis.49  
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 14 
 
As of February 2005, erlotinib has been studied clinically in more than 6,800 healthy 
subjects and cancer patients (excluding patients exposed to placebo) in a number of 
Phase I, II and III studies, including a large phase II study showing modest single-agent 
activity in advanced squamous cell carcinoma of the head and neck.91,92  
Erlotinib/Tarceva was approved by the US FDA for second- and third-line treatment of 
advanced or metastatic NSCLC at a dose of 150 mg daily.79  
 
Following oral administration in rats and dogs, erlotinib was rapidly absorbed (Tmax 1 to 2 
hours) with an oral bioavailability of 45% to 88%. Erlotinib displayed nonlinear 
pharmacokinetics, with greater than expected increases in Cmax and AUC with increasing 
doses. Repeat-dose studies showed no substantial changes in the pharmacokinetics of 
erlotinib over time. In vitro measurement of protein binding of erlotinib in animal and 
human plasma ranged from 85% to 95%. The primary route of metabolism was oxidation 
by CYP3A4. Erlotinib and its metabolites were excreted predominantly via the feces (> 
90%) with a small amount recovered in urine.  
 
Toxicology studies were conducted in mice, rats (up to 6 months), dogs (up to 1 year), 
and monkeys (1 week). Treatment-related effects observed in at least 1 species or study 
included effects on the cornea (atrophy and ulceration), skin (follicular degeneration and 
inflammation, redness, and alopecia), ovary (atrophy), liver (liver necrosis), kidney (renal 
papillary necrosis and tubular dilatation), and gastrointestinal tract (delayed gastric 
emptying and diarrhea). Red blood cells (RBC) parameters were decreased, and white 
blood cells (WBCs) primarily neutrophils, were increased. There were treatment-related 
increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 
bilirubin; increases in bilirubin were likely caused by treatment-related impairment of 
bilirubin metabolism.  
 
 
 
3. 
SUMMARY OF STUDY PLAN 
The proposed study will be a double-blinded, placebo-controlled randomized study to 
evaluate the chemopreventive effect of erlotinib in a high-risk group of oral IEN patients. 
The trial will be conducted at five centers in the United States:  M. D. Anderson Cancer 
Center, Memorial Sloan-Kettering Cancer Center, Emory University, the University of 
Chicago, and the University of Maryland.  There will be two categories of high-risk 
patients in this study:  (a) loss of heterozygosity (LOH) at 3p14 and/or 9p21 in the oral 
IEN of patients with a history of curatively treated oral cancer and (b) LOH at 3p14 
and/or 9p21 plus at one other chromosomal region in the IEN of patients with no oral 
cancer history. The trial will randomize 150 patients--75 will receive erlotinib (150 mg po 
QD) and 75 will receive matched placebo (po QD). The trial period is 4.5 years (including 
one-year treatment)--2 years to complete accrual and 2.5 more years of follow-up (mean 
of the additional follow-up period from 1.5 to 3.5 years).  A summary of the study 
schema appears below: 
Erlotinib (150 mg qd)
(N = 75)
Placebo
(N = 75)
Treatment
1 yr Rx
2.5 yrs FU
Endpoint
Oral
cancer
Screen
oral IEN pts
LOH
(accrual =
2 yrs)
S
t
r
a
t
i
f
y
R
a
n
d
o
m
i
z
e
No oral cancer history
35% risk/3 yrs
(N = 50)
Oral cancer history
65% risk/3 yrs
(N = 100)


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 15 
 
 
Once at the study site, informed consent will be obtained from willing participants, 
medical history will be obtained, oral lesions (if present) will be examined, blood samples 
will be taken, collection of archival tissue sample or biopsy of oral leukoplakia lesions for 
LOH analysis, and the epidemiologic and nutrition questionnaire (included in Appendix 
A) will be initiated.  Patients classified with oral leukoplakia and LOH with or without a 
prior history of cured oral cancer will be eligible for inclusion in the study and will be 
randomized into one of two groups.   
 
The primary endpoint of the trial will be the  oral cancer-free survival in patients receiving 
erlotinib as compared with the control group. Multiple secondary endpoints will be 
assessed as outlined in Section 1.2.  
 
4. 
PARTICIPANT SELECTION 
 
4.1 
Inclusion Criteria 
All the following conditions must be met before a patient can be included in the 
study: 
 
4.1.1 Male or female patients with one of the following: (a) loss of 
heterozygosity (LOH) at 3p14 and/or 9p21 in the oral IEN of patients with 
a history of curatively treated oral cancer or (b) LOH at 3p14 and/or 9p21 
plus at one other chromosomal region in the IEN of patients with no oral 
cancer history.   
4.1.2 Participants must have confirmed diagnosis of oral IEN lesion with LOH. 
(Note:The initial screening biopsy of oral IEN lesion with LOH must be 
obtained within 12 months of study enrollment.  If initial diagnostic biopsy 
for LOH is > 3 months prior to study enrollment, investigators may use 
clinical judgment to order an additional screening biopsy to assess 
histopathological changes). 
4.1.3 Age > 18 years 
4.1.4 ECOG performance status < 2  
4.1.5 Participants must have normal organ and marrow function as defined 
below within 30 days of randomization: 
CBC with differential white cell count – acceptable results must include: 
WBC > 3,000l, hemoglobin > 10 g/dl, platelet count > 125,000l 
 LFTs - total bilirubin and alkaline phosphatase, AST (SGOT) and ALT 
(SPGT) all within  < 1.5xULN. Note: At the discretion of the attending 
physician, participants with Gilbert’s disease may still be eligible to 
participate in the event the total bilirubin value is > 1.5xULN. 
 Kidney function - serum creatinine < 1.5xULN 
 Chemistry - Sodium and potassium all within normal institutional limits.  
  4.1.6 The effects of the study agent on the developing human fetus are 
unknown. For this reason, women of child-bearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of active 
treatment. Negative serum pregnancy test in women of child-bearing 
potential. Childbearing potential will be defined as women who have had 
menses within the past 12 months, who have not had tubal ligation or 
bilateral oophorectomy. Should a woman become pregnant or suspect 
she is pregnant while participating in this study, she should inform her 
study physician immediately. 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 16 
 
4.1.7 Ability to understand and the willingness to sign a written informed 
consent document 
 
4.2 
Exclusion Criteria 
 
4.2.1 Patients with active cancer or any cancer within the previous two years, 
excluding oral and non-melanoma skin cancer.  
4.2.2 Patients with acute intercurrent illness or who have had surgery, radiation 
therapy, or chemotherapy within the preceeding 4 weeks unless they 
have fully recovered.   
4.2.3 Patients with a documented history of coagulopathy and/or those taking 
warfarin or warfarin-derivative anticoagulants 
4.2.4 Women who are pregnant (confirmed by -HCG if applicable) or 
breastfeeding 
 
 4.2.5 Any medical or psychological condition or any reason that, according to 
the investigator’s judgment, makes the patient unsuitable for participation 
in the study 
4.2.6 Patients who have participated in other experimental therapy studies 
within 3 months of enrollment to this trial 
4.2.7 Patients with a history of inflammatory bowel disease 
4.2.8 Patients with a documented history of interstitial lung disease 
 
4.3 
Inclusion of Women and Minorities 
No patient will be excluded from the study on the basis of ethnicity, race, sex, or 
older age.  Most oral cavity cancers arise in patients above the age of 65, but the 
incidence in younger patients is increasing, i.e. including patients younger than 
50 years. The study subjects will be patients above 18 years of age, since oral 
IEN/cancer is extremely rare in children and the safety profile of erlotinib is 
unknown in this age group. Efforts will be made to recruit all minority participants 
identified with IEN and LOH.  
 
4.4 
Recruitment and Retention Plan 
Methodology, Infrastructure and Accrual 
The 20-years experience of M. D. Anderson Cancer Center (MDACC) in 
advancing the translational study of head and neck cancer chemoprevention in 
the settings of head and neck IEN and SPTs1,2,4,38,93-102 includes 9 trials in oral 
IEN, the majority of which were randomized, controlled and 5 of which were 
completed within the past 5 years.  With this experience, MDACC has 
established effective methodologies and a strong clinical, laboratory and accrual 
infrastructure for translational head-and-neck chemoprevention.  The majority of 
trial patients will be accrued at MDACC, with additional accrual from Memorial 
Sloan Kettering Cancer Center, Emory University, the University of Chicago, and 
the University of Maryland.  The estimated accrual figures for all participating 
centers are presented in Table 1 (relevant data and calculations follow the table): 
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 17 
 
Table 1.  Screenings and Randomizations by Quarter (Q). 
            
Year 1 
Year 2 
Year 3
   
Q1* 
Q2†
Q3 
Q4
Q1 
Q2
Q3 
Q4 
Q1‡ 
Screened 
26 
59 
72 
72 
59 
59
59 
59 
26 
Randomized 
8 
18 
22 
22 
18 
18
18 
18 
8 
* M. D. Anderson alone (while awaiting IRB approval at the 4 other sites); 
  begins with MDACC protocol activation. 
† The 4 other sites join M. D. Anderson in this quarter. 
‡ Total for 4 other sites; M. D. Anderson finished at end of Year 2. 
 
Quarter 1 (Q1) screenings (26) and accruals (8) in the table reflect trial activation 
at MDACC alone while the protocol is undergoing IRB review and approval at the 
other 3 clinical sites.  These sites begin screening and accrual in Q2 of Year 1 
and will complete accrual in Q1 of Year 3.  Each center will have a substantial 
cohort of potentially eligible patients in follow-up when the trial is activated.  
These patients will be captured (along with new patients) throughout the first year 
at each center.  We assume that 2/3 of the patients will have oral intraepithelial 
neoplasia (IEN) and a prior oral cancer and 1/3 will have oral IEN alone (no oral 
cancer history).  Among those with a prior cancer, 67% will have eligible LOH 
and 60% of these will consent to go on trial.  Therefore, the randomization “yield” 
among screening patients with oral IEN and a prior oral cancer is 0.67 x 0.60 = 
0.40.  On the other hand, among patients with oral IEN alone, 28% will have 
eligible LOH and 45% will consent to go on trial.  The randomization “yield” of 
these patients is 0.28 x 0.45 = 0.13.  Therefore, the overall yield is 0.67 x 0.40 + 
0.33 x 0.13 = 0.31.  Based on these assumptions, we will screen approximately 
491 patients in order to accrue 150 randomized patients at all 4 participating U.S. 
clinical sites. 
 
Accrual at MDACC 
There are no competing studies for the oral IEN patients in this study at M. D. 
Anderson Cancer Center, and the trial has the full support of the chairs of the 
departments of Thoracic/Head and Neck Medical Oncology and Head and Neck 
Surgery (which includes dental oncology).  As part of this collaboration, we have 
added this clinical protocol to an interactive database managed by the 
department of Head and Neck Surgery entitled "First Match." This matching 
database will alert research personnel of new patients with certain 
characteristics, i.e.,  oral cancer diagnosis, that have been evaluated in the Head 
and Neck Surgery clinic.  Through this mechanism, these patients may then be 
approached at the time of their follow-up visit to discuss possible participation in 
this clinical trial.    
 
Oral IEN/LOH Patients with Curatively Treated Cancer History:  MDACC sees 
300 oral cancer patients per year (actual average in past 5 years = 309), who are 
referred primarily by dentists and ear, nose and throat (ENT) specialists.  The 
eligible patients in this cohort are not eligible for any other protocols, have no 
standard treatment, and are continually followed by M. D. Anderson Cancer 
Center surgeons over the years.  These IEN with oral cancer history estimates 
are a collaboration of Drs. Lippman (Chair, Thoracic/Head and Neck Medical 
Oncology), Weber (Chair, Head and Neck Surgery), and Gillenwater (head and 
neck surgeon), and the Head and Neck Center database manager. 
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 18 
 
Oral IEN/LOH Patients with No Cancer History:  Patients with eligible IEN (based 
on LOH) and no history of cancer also have no standard treatment.  
Approximately 80 oral IEN patients (no cancer history) are registered within our 
current follow-up program within our Head and Neck Cancer SPORE and are 
available for recruitment to our trial.  We also evaluate approximately 50 new oral 
IEN (no prior cancer) patients per year in the MDACC Head and Neck Center.  
Screened patients who do not have the eligible LOH profile will be followed 
observationally (and prospectively) with biopsy as indicated to assess acquisition 
of LOH; if LOH is acquired, these patients become eligible for the trial.  
Furthermore, our head and neck team will move in Summer 2006 into a new 
Head and Neck Center, where Drs. Weber and Lippman will establish a 
comprehensive oral premalignancy/IEN program since oral IEN is a major 
research focus of both of their departments. 
 
Accrual at the University of Chicago, Memorial Sloan Kettering, Emory 
University, and the University of Maryland 
As does MDACC, our four partner accrual centers all have pre-eminent programs 
of head and neck cancer therapy and prevention practice and research, including 
active programs of chemoprevention in oral IEN.  The considerations for 
estimating accrual at each center are similar to those outlined above for MDACC.  
The conflicts between this trial and other trials are from none to minimal at these 
respective centers, and their accrual estimates have taken into account the 
portfolio of trials at each center.  
 
The University of Chicago Head and Neck program is a world renowned program 
with published experience in oral IEN trials.1,80,82,103  The collaborative history of 
MDACC with the University of Chicago includes a targeted-agent trial in oral 
IEN.103  Co-investigator Dr. Ezra Cohen, who will lead our clinical trial at the 
University of Chicago, is an expert in the area of EGFR targeting in 
clinical/translational trials in head and neck cancer.  Memorial Sloan Kettering 
has an outstanding Head and Neck cancer program and collaborates already 
with MDACC in our NCI N01 cancer chemoprevention consortium.  Co-
investigator Dr. Jay Boyle is a leader in targeted prevention in oral IEN104 and will 
lead our clinical trial at Memorial Sloan Kettering.  Dr. Boyle is PI of an N01 trial 
of an PPAR-gamma agonist in oral IEN and is a key collaborator with MDACC on 
the recently completed RCT of celecoxib in oral IEN. Emory University also has 
strong experience in head and neck cancer therapy and prevention under the 
leadership of Co-investigator Dr. Dong Shin, who is Director of the Clinical and 
Translational Cancer Prevention Program at Emory.  Dr. Shin has extensive 
experience in clinical/translational trials in oral IEN and in the setting of curatively 
treated head and neck cancer patients and has long-standing collaborations with 
head and neck investigators at M. D. Anderson Cancer Center, where he was a 
highly respected member of the faculty.52,84,95,105,106  Dr. Li Mao is one of the key 
architects for the current prevention trial and the key player for development of 
the genetic test used for selection of high risk patients in the clinical trial.  Dr. 
Mao has recently moved to University of Maryland Dental School to serve as 
Professor and Chairman, Department of Oncology and Diagnostic Sciences. 
 
LOH Screening 
Based on the strong data presented above in Molecular Risk and Cohort 
Selection, the previous section, we propose to use LOH status to select patients 
to participate in our prevention trial.  There will be two selection criteria.  IEN 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 19 
 
patients with no oral cancer history must have LOH at 3p14 and/or 9p21 plus at 
least one of the following regions: 17p, 8p, 11p, 4q, or 13q.  IEN patients with 
clinically cured oral cancer must have LOH at either 3p14 and/or 9p21 to be 
eligible for the study.   
 
Dr. Mao’s extensive data derived from small paraffin-embedded tissue samples 
of oral IENs and oral cancers demonstrate that using 2-3 microsatellite markers 
for each locus gives a > 95% informative test rate (deletion status could be 
interpreted).  We will use automatic capillary DNA analyzer (AB3100) to separate 
microsatellite alleles and to quantify peak heights of each alleles.  LOH is defined 
as the ratios of the peak heights of the two alleles in lesion (L1/L2) DNA and in 
the corresponding normal lymphocytes (N1/N2) DNA ≥1.43 or 0.7.  The 
extensive experience of Drs. Li Mao and Adel El-Naggar in this area of research 
ensures peak efficiency in the patient screening and selection process.  We have 
established that the LOH status of oral IENs can be determined within 7 business 
days, which will ensure timely enrollment of patients into our clinical trial. 
 
5. 
AGENT ADMINISTRATION 
Intervention will be administered on an outpatient basis. Reported adverse events and 
potential risks are described in Section 6.2 
 
5.1 
Dose Regimen and Dose Groups 
1) 
Erlotinib, 150 mg po QD  
2) 
Erlotinib placebo 
 
Patients will be on active, continuous treatment for 12 months  
 
5.2 
Rationale for Dose Selection 
Erlotinib 
The dose of 150 mg po QD of the EGFR inhibitor erlotinib was chosen for this 
trial based on strong supportive preclinical and clinical data including in the head 
and neck. The standard recommended dose of erlotinib approved by the FDA for 
treatment of NSCLC, another disease of the upper aerodigestive tract, is 150 mg 
po QD. This FDA-approved dose was based on the positive results of erlotinib in 
the BR21 trial, which was a multinational, placebo-controlled, double-blind phase 
III trial of second- or third-line therapy for advanced or metastatic NSCLC. A total 
of 731 patients were randomized to erlotinib at 150 mg per day versus placebo in 
a 2:1 randomization, and a subset of BR21 patients received erlotinib for > 1 
year.79  
 
Erlotinib at 150 mg/day produces plasma concentrations in patients that are 
equivalent to active erlotinib concentrations in preclinical head and neck and lung 
cancer models. A limited clinical study in cancers of the head and neck and lung 
indicated that erlotinib at 150 mg/day produced pathologic responses that 
correlated with higher tumor tissue concentrations of erlotinib and suppression of 
cyclin D1 (which is highly associated with oral cancer development, is 
upregulated by EGFR, is suppressed by erlotinib in vitro, and can be suppressed 
in association with oral cancer prevention49) and Ki67 in tissue samples of 
responding patients (versus samples of non-responding patients).67 
 
 
 


MDACC Protocol # 2003-0824 
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Page 20 
 
5.3 
Study Agent Administration 
Each patient will be required to take 1 tablet daily (unless there is a dose 
reduction, which is described in Section 10.3). Participants should take the study 
medication (erlotinib or its matched placebo) in the morning at approximately the 
same time every day. It is to be taken with up to 200 mL (~1 cup or 8 oz) of 
water, and should be taken 1 hour before or 2 hours after meals, other 
medications,  vitamins and iron supplements. Participants will be instructed not to 
drink grapefruit juice while on study drug as this is a CYP3A4 inhibitor. If the 
patient vomits after taking a study dose, the dose is replaced only if the tablet(s) 
can actually be seen (and counted). The scheme for dose reductions of both 
agents based on certain toxicity criteria are outlined in Section 10.3. 
 
5.4 
Concomitant Medication 
Erlotinib is both protein bound (92% to 95% in humans) and metabolized in the 
liver by CYP3A4 and, to a lesser extent, CYP1A2 and in the lungs by CYP1A1. A 
potential for drug-drug interactions exists when erlotinib is co-administered with 
drugs that are highly protein bound or that are CYP3A4 inhibitors/inducers. (See 
Appendix D). 
 
For patients who are being concomitantly treated with a potent CYP3A4 inhibitor, 
a dose reduction should be considered in the presence of severe adverse events. 
For patients who are being concomitantly treated with a potent CYP3A4 inducer, 
alternative treatments that lack potent CYP3A4-inducing properties should be 
considered. 
 
All medications (prescription and over-the-counter), vitamin and mineral 
supplements, and/or herbs taken by the participant will be documented on the 
concomitant medication source documentation and will include: 1) start and stop 
date, dose, route of administration, and indication. Medications taken for a 
procedure (e.g., biopsy) should also be included. 
 
5.5 
Compliance 
Compliance is defined as number of pills taken divided by number of pills that 
should have been taken measured by pill count. Patients will also be given a pill 
diary and will be instructed to keep the diary during the one-year treatment 
period. During clinical visits at 1, 3, 6, 9 and 12 months, patients will be instructed 
to bring in the bottles with remaining drugs (for pill count) and pill diary. New 
study medication will be dispensed and new pill diaries provided at months 1, 3, 
6 and 9. Compliance will be based on pill count and plasma trough levels. 
Information from the pill diary can supplement pill count to have a more accurate 
assessment of a patient’s compliance.  
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1 
Study Agent 
Erlotinib 
Chemistry: Erlotinib is chemically designated as N (3-ethynylphenyl)-6,7-bis (2-
methoxyethoxy)-4-quinazoliamine, monohydrochloride. The empirical formula for 
erlotinib is C22H23N3O4HCL. Erlotinib is an off-white to pale yellow powder. The 
pharmaceutical preparations of erlotinib are formulations containing the 
hydrochloride (HCl) salt. All clinical evaluations have investigated erlotinib HCl; 
doses were based on free base equivalents. Erlotinib is currently formulated as 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 21 
 
conventional, immediate-release tablets. Excipients in the formulation include 
lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, sodium 
lauryl sulfate and magnesium stearate.  
 
Supply: The 150 mg, 100 mg and 25 mg strengths are supplied as white film-
coated tablets for daily oral administration. All tablets are round with a biconvex 
face and straight sides. The 150 mg tablets are 13/32” (10 mm); the 100 mg 
tablets are 11/32” (9 mm); and the 25 mg tablets are 1/4” (6 mm). The lower 
doses (100 mg and 25 mg) will be used when dose reductions are necessary. 
Erlotinib tablets will be supplied in white, high-density polyethylene (HDPE) 
bottles. 
 
Storage: Erlotinib should be stored at temperatures between 15oC and 30oC 
(59oF and 86oF).  
 
Drug Accountability 
The investigator is ultimately responsible for the maintenance of records 
regarding the study drug receipt, dispensing, unused drug return by subjects. 
Institutions participating in this study have the responsibility of establishing a 
system to ensure that delivery of study medication is correctly received and 
recorded by a responsible party (e.g., a pharmacist), and that study medication is 
handled, dispensed and stored safely and properly. 
 
6.2 
Reported Adverse Events and Potential Risks 
Erlotinib 
Based on clinical results, rash (dermatosis), diarrhea, nausea, fatigue, stomatitis, 
vomiting, and headache were the most frequently reported toxicities with 
exposure to single-agent erlotinib. Patients receiving erlotinib in combination with 
various chemotherapy agents have generally experienced the same type of 
adverse events as with either agent alone.  
 
Common adverse events (occurring in 10%-25% of subjects) include dry or itchy 
skin, desquamation, dry eyes, decreased blood counts (which may lead to 
infection, bleeding and/or fatigue), dry mouth, nausea and vomiting, and 
anorexia. 
 
Laboratory abnormalities observed infrequently with erlotinib as a single agent 
primarily involve liver function tests, including elevation of ALT, AST, and/or 
bilirubin. 
 
There have been infrequent reports of serious interstitial lung disease (ILD)-like 
events (including fatalities) in patients receiving erlotinib for treatment of NSCLC, 
pancreatic cancer or other advanced solid tumors. In a single-agent study in 
patients with NSCLC, the incidence of ILD-like events (0.8%) was the same in 
the placebo and erlotinib groups. In a combination study with gemcitabine in 
patients with pancreatic cancer, the incidence of ILD-like events was 2.5% 
versus 0.4% in the erlotinib plus gemcitabine versus the placebo plus 
gemcitabine groups, respectively. The overall incidence in erlotinib-treated 
patients from all studies (including uncontrolled studies and studies with 
concurrent chemotherapy) is approximately 0.7% out of approximately 4,900 
patients. Reported diagnoses included pneumonitis, radiation pneumonitis, 
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 22 
 
obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, 
and lung infiltration. 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. No imbalance was noted in the incidence of ILD-like events between 
treatment groups in a single-agent, randomized, placebo-controlled  or in  2 large 
1st line NSCLC studies (Study OSI2298g, Study BO16411), which utilized a 
standard platinum-based regimen with or without erlotinib. However, that was not 
the case when erlotinib was used concurrently with gemcitabine in a placebo-
controlled study. Therefore, one cannot completely rule out a potential causal 
relationship between erlotinib exposure and the rare occurrence of ILD.  
 
In the event of acute onset of new or progressive, unexplained pulmonary 
symptoms such as dyspnea, cough, and fever, erlotinib therapy should be 
interrupted pending diagnostic evaluation. If ILD is diagnosed, erlotinib should be 
discontinued and appropriate treatment instituted as necessary. 
 
Erlotinib is protein bound (92% to 95% in humans). It is metabolized in the liver 
by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent 
CYP1A2, and the pulmonary isoform CYP1A1. Therefore, a potential for drug-
drug interaction exists when erlotinib is coadministered with drugs that are highly 
protein bound or that are potent CYP3A4 inhibitors/inducers (discussed in 
Section 5.4; examples listed in Appendix D). In addition to these possibilities, 
altered coagulation parameters and/or bleeding events (including fatalities) have 
been reported in patients receiving erlotinib either alone or in combination with 
other chemotherapeutic agents together with concomitant coumarin-derivative 
anticoagulants, including warfarin. The mechanism for this is still unknown.  
Additional information on clinically relevant enzyme inhibitors and enhancers can 
be found at http://medicine.iupui.edu/flockhart/ or www.drug-interactions.com. 
 
6.3 
Availability and Accountability 
OSI Pharmaceuticals will provide active substance of erlotinib and matched 
placebo in tablets. The packaged medication will be sent to the pharmacy at 
each participating center and each site will be responsible for: storing the trial 
medication and keeping accounts of all batch numbers in stock; keeping drug 
accountability records; re-labeling the study medication with required labels; and 
dispatching labeled medication to the patients while they are attending scheduled 
clinic visits. Unused study medication will be destroyed at the pharmacies of the 
study sites. 
 
6.4 
Dispensing 
Each patient will be provided with the study medication containing the active drug 
or the matched placebo to the active drug.   
 
6.5 
Randomization and Blinding 
Stratified randomization with dynamic allocation (see Section 12.2 for details) will 
be performed via the web-based database system.  A randomization algorithm 
will be developed and implemented by the Biostatistics and Data Management 
Core at M. D. Anderson Cancer Center.  Upon verifying the eligibility criteria and 
specifying the stratification factors, the research nurse at each site can 
randomize patients by pushing the “Randomize” button in the web-based 
database system.  Each randomization result will be sent directly to the site’s 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 23 
 
pharmacy.  Study participants, the sponsor, research nurses, and investigators 
will be blinded to the assigned treatment.  For verification of study randomization 
procedures, the sponsor may submit a formal request to the study statistician to 
obtain the blinded treatment assignments for study participants.   
 
The pharmacies will blind the study medication by inserting the name and patient 
number on the pre-printed labels (on medication bottles) and then by removing 
the tear-off portion of the label containing the correct information regarding the 
study medication.  This tear-off portion will be transferred to a form (one for each 
patient) and filed.  Only pharmacy personnel and the study monitor will have 
access to this file.  The patient will then be administered blinded medication. 
 
Unblinding 
Unblinding of single cases by the sponsor and/or investigator will only be 
performed if relevant for the safety of the participant. In emergency situations, the 
investigator would contact the sponsor, who would contact the study statistician 
and local pharmacy to obtain immediate blinding information for the participant.  
The sponsor would then pass this information on to the investigator to enable the 
participant to be treated.  In non-emergency situations, the same procedures 
would apply, however the study statistician and the study sponsor will discuss 
and evaluate the request, then, would be responsible for making the decision of 
whether or not to unblind. 
 
Unblinding of all participants will occur at the end of study, whereby the sponsor 
and investigators will be provided with a list containing data on which arms each 
of his/her patients were randomized to.  All unblinded cases should be reported 
to the US NCI. 
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 24  
 
 
 
7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Events  
 
Evaluation/ 
Procedure a 
Baseline 
/Pre-
Study 
Randomization
Month 
1 
Month 
3 
Month 
6 
Month  
9  
Month 12 or 
Early 
Termination 
Follow-Up 
Visits 
(every 6 
months)
Informed Consent 
X 
 
Assess Eligibility 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Smoking Status, Alcohol 
Usage 
X 
 
X 
X 
X 
X 
X 
X 
Epidemiologic/Nutrition 
Questionnaires 
X 
 
 
 
 
 
 
 Xk 
Physical Examb 
X 
 
X 
X 
X 
X 
X 
X 
Vital Signs: 
Temperature,BP, Pulse, 
Respiration 
X 
 
X 
X 
X 
X 
X 
X 
Hematology/Chemistryc 
X 
 
X 
X 
X 
X 
X 
X 
Serum -HCG Pregnancy 
Testd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Examination of Oral 
Cavity 
X 
 
X 
X 
X 
X 
X 
X 
Biopsiese 
X 
 
 
Xm 
 
 
Xm 
 
Biomarkersf 
X 
 
 
X 
X 
 
X 
Xl 
Plasma Trough Levelsg 
X 
 
 
X 
X 
 
X 
 
Concomitant 
Medication Review 
X 
 
X 
X 
X 
X 
X 
X 
Dispense Study Agenth 
 
X
X
X
X
X 
Collect Study Agenti 
 
 
X 
X 
X 
X 
X 
 
Review Agent 
Diary/Recordj 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events and 
Symptom Assessments 
 
 
X 
X 
X 
X 
X 
X 


MDACC protocol # 2003-0824 
Revised May 24, 2010 
 
Page 25 
 
a 
Baseline evaluations should be conducted within 30 days prior to initiating study treatment 
unless otherwise specified.  On-Study evaluations may be conducted within the  following 
timeframes: Months 1 and 3: +/- 7 days of the date specified in the protocol; Months 6, 9, and 
12: +/- 14 days of the date specified in the protocol; Follow-Up Visits: within 60 days of the 
date specified in the protocol. 
b 
Full physical exam to include performance status (at baseline to determine eligibility) and vital 
signs (including temperature, blood pressure, pulse, and respiration). 
c 
Hematology and chemistry will be done at baseline, months 1, 3, 6, 9, and 12 then Q6 months 
thereafter until completion of follow-up period.  These will include the following: SGPT, SGOT, 
alkaline phosphatase, bilirubin, creatinine, sodium, potassium, magnesium, albumin, 
hemoglobin, hematocrit, platelet count, CBC with differential, and WBC. 
d 
Serum -HCG in women of child-bearing potential at baseline within 14 days of initiating study 
treatment 
e 
Biopsies of lesions at baseline (Biopsy will only be obtained if initial diagnostic biopsy of LOH 
is > 12 months prior to study enrollment or unavailable), month 3, and month12 or early 
termination. 
f 
Baseline blood collection for isolation of lymphocytes and biomarker assays. On-study blood 
collection for biomarker assays at months 3, 6, and 12 then Q12 months thereafter until 
completion of follow-up period 
g 
Plasma trough levels will be done at baseline, month 3, month 6 and month 12 
h 
Study medication and pill diaries will be dispensed at randomization and during clinic visits at 
months 1,3, 6 and 9 
i 
Unused study medication and completed pill diaries will be collected during clinic visits at 
months 1, 3, 6, 9 and 12 
j 
Review of pill diaries and compliance will be done during clinic visits 
k 
At final clinic visit 
l 
Every Q12 months (Months 24 and 36) during the follow-up period  
m 
For patients with visible oral leukoplakia lesions, quantitation of lesions, bidimensional 
measurements, and biopsy will be obtained. For patients with no visible oral leukoplakia 
lesions, a biopsy will be obtained at the site of the previous lesion biopsy or at mucosa 
adjacent to cancer resection. 
 
 
7.2 
Baseline Testing/Pre-Study Evaluation 
Following an introduction to the nature of the study, the study physician and 
research coordinator will evaluate each individual for enrollment. Baseline 
evaluations (with the exception of the study questionnaire) should be 
conducted within 30 days prior to initiating study treatment unless otherwise 
specified.  
 
This will include: 
 
7.2.1 Review of medical records for eligibility 
7.2.2 Discussion of the risks, benefits, goals and limitations of the study and 
any alternate treatments that may be available with the subject. 
7.2.3 Review of inclusion and exclusion criteria 
7.2.4 Review of the informed consent process and form 
7.2.5 Acquisition of informed consent and registration into study 
7.2.6 Physical examination and examination of oral cavity (including 
baseline quantitation and bidimensional measurements of visible 
lesions) 
7.2.7 Mucosal biopsies for histological analysis and LOH status.  
 Note: Biopsy will only be obtained if initial diagnostic biopsy of LOH is 
> 12 months prior to study enrollment or unavailable. If initial 
diagnostic biopsy for LOH is > 3 months prior to study enrollment, 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 26 
 
investigators may use clinical judgment to order an additional 
screening biopsy to assess histopathological changes.  
7.2.8  Symptom assessment and concomitant medication review  
 
7.2.9 Study 
questionnaire 
(tobacco 
consumption, 
alcohol 
use, 
demographics, nutrition). Note: The research team will make every 
attempt to initiate the questionnaire within 30 days of beginning study 
treatment  
7.2.10 Medical history (including smoking status and alcohol usage) 
7.2.11 SGPT, SGOT, alkaline phosphatase, bilirubin, creatinine, sodium, 
potassium, magnesium, albumin, hemoglobin, hematocrit, platelet 
count, CBC with differential, WBC, and serum ßHCG in females of 
childbearing potential (within 14 days of randomization). 
7.2.12 Plasma drug trough assessment. This will be used as a baseline for 
each patient on which subsequent trough levels will be compared. 
7.2.13 Family history of cancer 
7.2.14  Blood collection for isolation of lymphocytes and biomarker analysis 
 
7.3 
Randomization 
Upon verifying the eligibility criteria, the research nurse at each site can 
randomize patients by pushing the “Randomize” button in the web-based 
database system.  Each randomization result will be sent directly to the site’s 
pharmacy.  Study participants, the sponsor, research nurses, and 
investigators will be blinded to the assigned treatment. 
 
7.3.1 Study medication dispensed 
 
7.3.2 Pill diary and instructions dispensed 
 
7.4 
On-Study Evaluations (Active Treatment Period) 
 
7.4.1 Months 1-3 (within +/- 7 days) clinic visits at months 1 and 3 to include 
full physical examination, examination of the oral cavity, hematology 
and chemistry, smoking status, alcohol usage, blood for biomarker 
assays and plasma trough levels (at month 3 visit), concomitant 
medication review, adverse event and symptom assessment, return of 
completed pill diaries and unused medication returned, new 
medication and pill diaries dispensed. For patients with visible oral 
leukoplakia 
lesions, 
quantitation 
of 
lesions, 
bidimensional 
measurements, and biopsy will be obtained at month 3. For patients 
with no visible oral leukoplakia lesions, a biopsy will be obtained at the 
site of the previous lesion biopsy or at mucosa adjacent to cancer 
resection at month 3. 
 
7.4.2 
Months 4 – 11 (within +/- 14 days) clinic visits at months 6 and 9 to 
include full physical examination, examination of the oral cavity, 
hematology and chemistry, smoking status, alcohol usage, blood for 
biomarker assays and plasma trough levels (at month 6 visit), 
concomitant medication review, adverse event and symptom 
assessment, return of completed pill diaries and unused medication 
returned, new medication and pill diaries dispensed.  
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 27 
 
7.4.3 Month 12 (within +/- 14 days) or Early Termination to include full 
physical examination, examination of the oral cavity,  hematology, 
chemistry, smoking status, alcohol usage, blood for biomarker assays 
 and plasma trough levels, concomitant medication review, adverse 
event and symptom assessment, return of completed pill diaries and 
unused medication. For patients with visible oral leukoplakia lesions, 
quantitation of lesions, bidimensional measurements, and biopsy will 
be obtained. For patients with no visible oral leukoplakia lesions, a 
biopsy will be obtained at the site of the previous lesion biopsy or at 
mucosa adjacent to cancer resection. 
 
7.5 
Follow-up (End of the active treatment period until patients are placed off 
study) 
 
7.5.1 Every six months (within 60 days):  Full physical examination, 
examination of the oral cavity, smoking status, alcohol usage, 
hematology, chemistry, blood for biomarker assays (at months 24 and 
month 36) and symptom assessment. 
7.5.2 Final visit: Full physical examination, examination of the oral cavity, 
smoking status, alcohol usage, hematology, chemistry, blood for 
biomarker assays, symptom assessment and epidemiological/nutrition 
questionnaires. 
 
7.6 
Long-term Follow-up (continued evaluation from initial participation until after 
the study is completed) 
 
All patients who signed a written informed consent document (or their family 
members/designees), even if they were not subsequently randomized to one 
of the treatment arms for any reason, may be contacted by the research team 
(during clinic visits, by telephone, in writing, by electronic mail or by other 
method of communication) to confirm or provide clinical information on long-
term follow-up.  Participants’ medical records may also be reviewed to obtain 
long-term follow-up information.  This will allow for a better estimation, for 
example, of rates of invasive cancer in patients whose lesions harbor LOH or 
not.  
 
7.7 
Methods for Clinical Procedures 
Clinical Investigation of Oral Cavity 
Examination of the oral cavity will be conducted at each scheduled clinic visit.  
Leukoplakias that have increased in size or new leukoplakias will be biopsied 
at the discretion of the investigator.  Leukoplakias will be monitored at each 
scheduled clinic visit and bi-dimensional measurements of the visible lesions 
will be performed as indicated on the study schema and study schedule of 
events (section 7).  
 
Epidemiological Data 
Baseline and follow-up epidemiologic and nutrition data will be collected by 
means of a structured questionnaire.  Participants at M.D. Anderson Cancer 
Center will have the questionnaire administered during a 90-minute interview. 
All interviewers will be trained on specific interviewing techniques concerning 
the questionnaire, as well as general interviewing techniques (including 
leading and probing) to ensure accuracy and consistency of collected data.  


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 28 
 
Five percent of interviews will be re-conducted by a trained back-up 
interviewer to confirm consistency of collected data. Quality assurance/quality 
control will be assured by coding the data and removing all personal 
identifiers; keying coded data into a single password-protected database; 
utilizing a data edit check program; and by storing hard copies from all 
recruitment sites at M. D. Anderson Cancer Center.   
 
The Epidemiologic Questionnaire Database will contain entered data from 
completed epidemiologic and nutrition questionnaires. Hard copies of the 
epidemiologic and nutrition questionnaires will be filled out during an interview 
initiated at baseline and at the completion of the follow-up period. Participants 
at University of Chicago, Memorial Sloan-Kettering, Emory University – 
Winship Cancer Institute, and the University of Maryland will submit the 
original questionnaires to Dr. Jie Lin at the following address to be edit 
checked and entered into the Epidemiologic Questionnaire Database:  
 
Dr. Jie Lin 
U.T. M. D. Anderson Cancer Center 
Department of Epidemiology 
1155 Herman P. Pressler Street, Unit 1340 
Houston, Texas 77030 
  
 
 
The original will be stored in a locked file at M. D. Anderson Cancer Center 
following data entry.  
 
 
Blood and Tissue Samples 
If initial diagnostic tissue sample for LOH is > 12 months prior to study 
enrollment or unavailable, a biopsy sample will be taken from at least one 
existing lesion.  Biopsy samples may be taken from all existing lesions at the 
discretion of the attending physician. The biopsies should be a minimum of 4-
5 millimeters in diameter. If the entire lesion is excised at baseline, 
subsequent biopsies will be performed on normal appearing mucosa at the 
same site as clinically indicated. The biopsies will be partitioned for snap 
freezing and for fixation in 10% formalin immediately. Please note:  Archival 
diagnostic tissue specimens obtained for LOH analysis will not be processed 
for snap freezing.  All biopsy specimens (initial screening biopsy for LOH 
analysis and subsequent biopsy specimens) from Memorial Sloan Kettering 
Cancer Center, Emory University, University of Chicago, and the University of 
Maryland will be ONLY prepared for fixation (see Appendix G).  
 
LOH investigations are performed on at least one sample taken (see “LOH 
Screening” section for details). 
 
Blood - 10 cc’s of blood (1-5cc EDTA tube and 1-5cc SST tube) will be drawn 
at each baseline, on-study and follow-up visit for analysis of routine laboratory 
parameters as listed in Section 7.  40 cc’s of blood (3-10 cc heparinized tubes 
and 1-10cc EDTA tube) will be drawn at the pre-study blood draw for isolation 
of lymphocytes.  10 cc’s of blood (1-10cc EDTA tube) will also be drawn at 
specified on-study visits for biomarker analysis and plasma trough levels.  


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 29 
 
Blood samples and biopsy specimens will be collected and shipped as  
detailed in Appendix G.  
 
The specimens and data used for clinical patient management and for 
ascertaining response to treatment on this protocol will also be processed and 
shipped to support interactive research projects at M. D. Anderson Cancer 
Center.  No data or specimens will be used until the protocol for their use has 
been submitted to and approved by the Institutional Review Boards at M. D. 
Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Emory 
University, University of Chicago, and University of Maryland. No data or 
specimens will be transferred to any other institution/party without the 
patient’s own consent. Confidentiality and patient anonymity will be assured 
through the assignment of unique and unrelated pathology numbers to each 
specimen as it is collected.  The name of each subject will be available only in 
a password-protected database. 
 
The data and specimens to be processed and shipped for research purposes 
include serum, PBLs, tissue, including surgical specimens of cancer tissue 
from patients who develop cancer during the clinical trial, and epidemiologic 
and clinical data, including information regarding patient outcome, survival 
and treatment.  All samples and data will be protected and kept confidential 
as described above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
An objective clinical response will be considered complete when gross inspection 
reveals no evidence of lesion(s) and will be considered partial when the product of 
bidimensional (perpendicular) millimeter measurements of the lesion or, if there are 
multiple lesions, the sum of the product of bidimensional measurements of all lesions 
MDACC, MSKCC, Emory University, University of Chicago, and University of Maryland 
Oral Tissue (fresh, frozen and fixed), serum, and PBLs 
Core C (MDACC)
Bl od, tissue 
Project 4 (MDACC) 
PBLs 
Project 2 (MDACC)
Fresh oral tissue 
Project 3 (MDACC) 
Serum (proteomics), oral tissue 
Pharmacology 
Services 
(MDACC)
Pathology 
Services 
(MDACC) ~
 
  
 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 30 
 
decreases by at least 50 percent. Lesions will be considered stable when the sum 
areas of all lesions combined increases by less than 25 percent or decreases by less 
than 50 percent. Disease progression will be defined as an increase of at least 25 
percent in the total area of all lesions combined during treatment or as the 
appearance of any new lesion. Although we will collect histologic data on oral 
leukoplakia lesions, these data will not be included in the response assessments but 
will be available for exploratory analyses. 
 
8.1 
Primary Endpoint 
The primary endpoint for the randomized trial will be oral cancer-free survival. 
 
8.2 
Planned Secondary Endpoints and Analytical Methods 
 
8.2.1 The size (bi-dimensional measurements) of oral IEN will be assessed 
and will be correlated with reduction in cancer risk. All oral lesions will 
be numbered and drawn onto a standardized diagram. 
8.2.2 Toxicities associated with therapy will be assessed during the active 
treatment period. We will employ a rigorous monitoring plan for all 
participants and will include frequent clinic visits, assessment of 
symptoms, surveillance labs and measurement of drug trough levels.  
8.2.3 We will assess molecular markers for correlations with oral cancer 
development in our oral leukoplakia patients. They will include (but are 
not restricted to): 
 
8.2.3.1 
EGFR, phospho-EGFR, TGF-alpha, ERK1/2, phospho-
ERK1/2, AKT, phospho-AKT, COX-2, STAT3, phospho-
STAT3, cyclin D1, HER2, Ki67, TUNEL, RAR-beta, hTERT, 
E-cadherin, 
P-cadherin, 
vimentin, 
Src, 
phospho-Src, 
cytokeratin.  All these markers will be assessed in oral 
tissue 
biopsy 
specimens 
via 
immunohistochemistry 
laboratory analyses, except for RAR-beta and hTERT, 
which will be assessed via RNA in situ hybridization. 
8.2.3.2 
EGFR gene copy number, will be measured by real-time Q-
PCR. 
8.2.3.3 
PGE2 levels.  This marker will be measured by high-
performance 
liquid 
chromatography 
(HPLC) 
mass-
spectrometry in frozen oral tissue biopsy specimens. 
8.2.3.4 
Perform computerized DNA image analysis of DNA content 
and ploidy evaluation and interpretation 
8.2.3.5 
Promoter methylation in p16 and in FHIT.  These markers 
will be assessed via methylation-specific PCR (MSP) in 
oral tissue biopsy specimens.  
8.2.3.6 
Protein profiling, which will be assessed via SELDI mass-
spectroscopy in serum specimens.  
8.2.3.7 
Chromosome-9related levels of chromosome polysomy, 
chromosome index, and fraction of cells involved in 
subclonal outgrowth.  These markers will be determined via 
chromosomal in situ hybridization (CISH) in oral tissue 
biopsy specimens. 
8.2.3.8 
BPDE-induced genetic damage, which will be measured by 
the Komet 4.0 image system in peripheral blood 
lymphocytes. 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 31 
 
8.2.3.9 
Estimated frequencies of polymorphisms in the following 
DNArepair genes implicated in the nucleotide excision 
repair (NER) pathway:  ERCC1, XPC, XPD/ERCC2, 
EXPF/ERC4, XPA, RAD23B, CLNH, ERCC5, LIG1.  These 
polymorphisms will be assessed via DNA extraction and 
genotyping techniques in peripheral blood lymphocytes.  
8.2.3.10 
Frequencies of BPDE chromosomal aberrations on 3p12.3, 
3p14.2, 3p21.3 and 3p25.2.  These markers will be 
determined by fluorescence in situ hybridization (FISH) 
with several probes on 3p in peripheral blood lymphocytes. 
8.2.3.11 
Polymorphisms of CYP1A1, CYP3A4, CCND1, COX-2, 
EGFR, and ErbB-2.  These polymorphisms will be explored 
via DNA extraction and genotyping techniques in peripheral 
blood lymphocytes. 
            8.2.3.12 
Genome wide single nucleotide polymorphisms, telomere 
length, mitochondrial DNA alterations 
 
 
8.2.4 Other Time-to-Event Endpoints 
 
8.2.4.1 
Overall survival. Overall survival is defined as time from 
randomization to death of any cause. If patients are alive at 
the end of study, the censoring time is set at the last follow 
up time. 
8.2.4.2 
Cancer-specific survival. Cancer-specific survival is defined 
as time from randomization to cancer specific death. If 
patients die of non-cancer cause or are alive at the end of 
study, the censoring time is set at the non-cancer death 
date or the last follow-up time. 
 
8.3 
Off Agent Criteria 
Patients who have been included may discontinue the study agent for general 
reasons (Declaration of Helsinki) or for safety reasons. A patient has the right 
to discontinue the study agent without having to give an explanation and 
without any negative effect on further treatment.  
 
All participants discontinuing the study agent prior to normal completion 
(normal completion will be defined as 12 consecutive months from study 
treatment initiation) will be asked to return to the study site for all remaining 
clinic visits and follow-up visits according to the schedule of events (Section 
7.1), except for patients discontinuing treatment due to diagnosis of oral 
cancer.  
 
Patients may stop taking study medications for the following reasons: 
 Completed the protocol-prescribed intervention 
 Adverse event or serious adverse event that is unacceptable to the patient 
or physician 
 Repeated grade 2 or greater toxicities or grade 4 toxicity that is believed to 
be possibly, probably or definitely related to study medication 
 Disease progression requiring alternative therapy in the opinion of the 
Principal Investigator 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 32 
 
 Pregnancy 
 Inadequate agent supply 
 Allergic reaction to the study medication(s) 
 Noncompliance  
 Patient desire to stop taking medication 
 Concomitant medications or medical contraindications. 
 
Patients may resume treatment if the following criteria are met: 
 Patients are within the normal treatment period (i.e. within 12 consecutive 
months from treatment initiation) 
 The reason for treatment discontinuation was not a grade 4 toxicity 
determined to be possibly, probably, or definitely related to the study 
treatment, or diagnosis of oral cancer 
 There is no other reason for withholding the study treatment in the 
Principal Investigator’s opinion 
 
8.4 
Off-Study Criteria 
Patients may go off-study for the following reasons:  
 The protocol intervention and any protocol-required follow-up period is 
completed 
 Diagnosis of cancer 
 Lost to follow-up 
 Withdraw consent 
 Death. 
 
Patients that have been placed off study will be asked to return to the study site for 
an early termination visit according to the schedule of events (Section 7.1).  
 
8.5 
Study Termination 
The NCI or regulatory agencies may discontinue the investigation at any time. 
 
9. 
REPORTING ADVERSE EVENTS 
Definition: 
An adverse event (AE) is an untoward medical occurrence in a study 
participant. An AE does not necessarily have a casual relationship with the treatment 
or study participant. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally 
associated with participation in a study, whether or not related to that participation. 
This includes all deaths that can occur while a participant is on a study. The NCI 
Common Toxicity Criteria (v3.0CTCAE), Appendix E) will guide grading of adverse 
events and dose reductions. 
 
A list of adverse events that have occurred or might occur can be found in Section 
6.2. 
 
9.1 
Adverse Events 
 
9.1.1 Reportable Adverse Events 
All adverse events that occur after the informed consent is signed and 
within 30 days after the last dose of study drug must be recorded on 
the adverse event source document whether or not related to study 
agent. Adverse events will be spontaneously reported by the patients, 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 33 
 
observed by the investigators, or elicited by the investigator by asking 
the patients specific questions according to a predefined scheme. The 
investigator is responsible for assuring that there are procedures and 
expertise available to deal with emergency situations during 
procedures related to the study. 
 
9.1.2 AE Data Elements 
 
Verbatim description of event 
 
Severity of AE 
 
Event onset date and ended date of AE (duration) 
 
Relationship to study drug 
 
Whether or not the event was reported as a Serious Adverse 
Event (SAE) 
 
 
9.1.3 Severity of AEs 
Adverse events not listed in the NCI Common Toxicity Criteria (v.3.0) 
will be assessed according to their impact on the participant’s ability to 
perform daily activities as follows: 
 
Severity 
Description 
Mild 
 
Barely noticeable, does not influence functioning 
 
Causing no limitations of usual activities 
Moderate 
 
Makes participant uncomfortable, influences functioning 
 
Causes some limitations of usual activities 
Severe 
 
Severe discomfort, treatment needed 
 
Severe and undesirable, causing inability to carry out 
usual activities 
Life Threatening 
 
Immediate risk of death 
 
Life threatening or disabling
Fatal 
 
Causes death of participant 
 
9.1.4 Follow-up of Adverse Events 
 
All adverse events, including lab abnormalities that in the opinion of 
the investigator are clinically significant, will be followed according to 
good medical practices and documented as such. 
 
9.2 
Serious Adverse Events 
 
9.2.1 Definition: 
ICH Guideline E2A and Fed. Reg. 62, Oct. 7, 1997 
define serious adverse events as those events, occurring at any dose, 
which meet any of the following criteria: 
 
Results in death 
 
Is life threatening (Note: the term life-threatening refers to an event 
in which the patient was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused 
death if it were more severe). 
 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
 
Results in persistent or significant disability/incapacity 


MDACC Protocol # 2003-0824 
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Page 34 
 
 
Is a congenital abnormality/birth defect 
 
Events that may not meet these criteria, but which the investigator 
finds very unusual and/or potentially serious, will also be reported 
in the same manner 
 
9.2.2 Reporting Serious Adverse Events 
All participating centers will report SAEs to their respective IRBs within 
5 working days of knowledge of the event and will simultaneously 
submit a copy of the SAE report to the IND sponsor (MDACC). Each 
center will report all deaths to their respective IRBs within 24 hours of 
knowledge of the event and will simultaneously submit a copy of the 
SAE report to the IND sponsor (MDACC). The IND sponsor will notify 
the NCI and OSI Pharmaceuticals within 24 hours of learning of the 
SAE to the following contacts: 
 
 
OSI Pharmaceuticals:  fax to OSI Drug Safety at 303-546-7706 
(for questions related to safety reporting, call OSI Drug Safety at 
303-546-7869) 
 
NCI: fax 
 
 
MDACC: Please email the SAE form to 
mdaccsafetyreports@mdanderson.org 
(E-mail must be sent from the PI’s email address or the PI must be 
copied on the e-mail containing the form). 
For problems sending the form or other questions, please contact 
 
 
The IND sponsor will also process and submit any required safety 
information to the FDA as required by CFR 312.32 ”IND Safety 
Report.” 
 
All adverse events will be followed until the patient outcome has been 
established. To ensure the safety of study participants, all SAEs will 
also be reported to the Data and Safety Monitoring Board (DSMB) at 
M. D. Anderson Cancer Center.  
 
10. 
MANAGING ADVERSE EVENTS/TOXICITIES/EARLY TERMINATIONS 
 
10.1 
Adverse Events 
Study participants will be monitored for all adverse events. All adverse events 
will be recorded in the source documentation. 
 
Persons included in the study will be monitored for adverse events during 
telephone contacts and clinic visits. Patients will also be provided with a 
telephone number at which they can reach the study coordinator, research 
nurse or principal investigator.  The range of adverse events possible in any 
clinical investigation is extensive and patients enrolled in this study will be 
carefully monitored. Particular attention will be paid to  
a) 
Diarrhea 
b) 
Rash 
c) 
Psychological side-effects as insomnia 
d) 
Signs and symptoms of ILD  


MDACC Protocol # 2003-0824 
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e) 
Eye disorders 
f) 
Anorexia 
g) 
Nausea  
h) 
Vomiting  
i) 
Hepatotoxicity 
 
Potential hepatotoxicity from erlotinib will be monitored with periodic liver 
function testing (transaminases, bilirubin, and alkaline phosphatase); erlotinib 
dose reductions, as described in Section 10.3, will be implemented if 
warranted by changes in liver function.   
 
Management of Adverse Events: 
Skin rash or dermatosis has been observed during the first several days of 
treatment with erlotinib in many patients and has been noted to diminish in 
severity despite continued treatment. Patients who develop a rash 
characterized by pustules or raised red areas may be treated with oral 
minocycline (100 mg BID for 7–10 days to a maximum of 150 mg BID for 7–
10 days as clinically indicated) at the discretion of the Investigator.  
Minocycline is known to interfere with anticoagulants and oral contraceptives.  
Patients treated with minocycline who are taking anticoagulants and/or oral 
contraceptives should be monitored accordingly. 
 
Patients with acute onset of new or progressive, unexplained pulmonary 
symptoms such as dyspnea, cough, and fever should have treatment held 
pending diagnostic evaluation.  If ILD is diagnosed, erlotinib should be 
discontinued and appropriate treatment instituted as necessary. 
 
10.2 
Causal Relationship of AE to Study Medication 
The causal relationship of the adverse event to the study medication will be 
assessed as one of the following: 
 
Unrelated:  
 
does not follow a reasonable temporal sequence following administration 
of the treatment drug 
Unlikely: 
 
could readily be produced by other medication administered to the patient 
or other, environmental factors the patient has been exposed to 
 
has previously been causally related to other drugs the patient is taking 
 
does not follow a normal response pattern to the treatment drug 
Possible: 
 
follows a reasonable temporal sequence following administration of the 
treatment drug 
Probable: 
 
follows a typical temporal sequence following administration of the 
treatment drug 
Definite:  
 
follows a known pattern of response to the treatment drug 
 
10.3 
Toxicity Attribution and Dose Reduction 
Study medication will be held then restarted for grade 3 or 4 toxicities as 
outlined in the table below. If the patient experiences grade 3 toxicity on the 


MDACC Protocol # 2003-0824 
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Page 36 
 
lowest doses, the patient will be taken off agent. There will be no dose 
escalation after dose reduction. Patients will not be taken off agent 
permanently if the SAE is clearly unrelated to the study medication. Dose 
reduction or stopping drug is also an option for grades 1 and 2 toxicities, 
irrespective of attribution to the study medication, that are unacceptable to the 
participant or physician. 


MDACC Protocol # 2003-0824 
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Page 37 
 
Toxicity Attribution 
Grade of 
Toxicity  
Is Toxicity Associated with Drug Treatment 
 
Unrelated 
Unlikely 
Possibly 
Probably 
Definitely 
Grade 0 
C 
C 
C 
C 
C 
Grade 1 
C 
C 
C 
C 
C 
Grade 2  
C 
C 
C 
C 
C 
Grade 3 
S-R0 
S-R0 
S-R-1 
S-R-1 
S-R-1 
Grade 4 
S-R0 
S-R0 
W 
W 
W 
     C  = Continue drug 
S-R0 = Stop drug until toxicity reaches grade 1 or lower, then restart drugs at the same 
doses 
S-R-1 = Stop drug until toxicity reaches grade 1 or lower, then restart drug at the next 
lower dose level (100 mg QD for erlotinib). The most common adverse events 
associated with erlotinib are rash (the most frequent) and diarrhea. If these 
adverse events do not resolve after the initial dose reduction, second dose 
reductions of erlotinib to 50 mg po QD are acceptable. After the second dose 
reductions, no further reductions will be permitted and patients with returning 
toxicities will be removed from the study. 
     W = Withdraw from trial  
 
 
11. 
STUDY MONITORING 
The investigator will be visited on a regular basis by the Clinical Study Monitor, who 
will check completed source documentation, discuss the progress of the study and 
monitor drug according to good clinical practice (GCP). The monitoring will also 
include source data verification (SDV).   
 
Source Data Verifications 
Monitor and/or regulatory authorities will be allowed audits at the investigation site for 
the purpose of source data verification, in which a case review of those parts of the 
hospital records relevant to the study must be required. Data recorded in the CRF 
must be current at the time of the scheduled monitoring visit. 
 
The Principal Investigator (Scott Lippman,M.D. M.D. Anderson Cancer Center) will 
be responsible for writing the protocol, ensuring any modifications to the study 
protocol must be reviewed and approved by the NCI prior to implementation, and for 
publishing study results.   
 
The Protocol Lead Investigator is responsible for reviewing all case report forms and 
documenting his/her review on evaluation forms, discussing the contents of the 
reports with the Statistician, and for publishing study results. He/She will, together 
with the study group, be responsible for data cleaning.  He/She will also generally be 
responsible for answering all clinical questions concerning eligibility, treatment, and 
the evaluation of the patients. He/She is responsible for arranging for the retention of 
the patient identification and the code list for at least 15 years after completion of the 
study. Patient files and other source data shall be kept for a maximum period of time 
permitted by each hospital. All information concerning the study should be stored in 
safe places inaccessible to unauthorized personnel. Unique study IDs will be 
assigned to identify the study participants. The cross-reference of study ID and 
patient ID will be stored in a secure file at each site and will be accessible only to 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 38 
 
authorized personnel. All the subsequent study coordination including information 
sent to M. D. Anderson Cancer Center will be based on study ID to protect the 
patient confidentiality.  
 
Treatment termination for any reason except completion of the study will be fully 
documented in the source documentation. Patients leaving the study before end-
point should, if possible, go through the same final evaluations as patients 
completing the study according to the protocol. Every reasonable effort should be 
made to maintain patient’s protocol compliance and participation in the study. The 
investigator will monitor patient protocol compliance at each follow-up visit. 
 
Should a patient discontinue the study for any reason, the patients should be urged 
to return for a final visit (with an early termination evaluation preferably performed 
within 14 days after discontinuation from the study). 
 
The IND sponsor and the National Cancer Institute will approve changes to the 
protocol or discontinuation of the study. Amendments or discontinuation of the study 
will be forwarded to each site for review and approval by their respective IRBs.  
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design  
The basic trial design is described earlier.  The proposed study will be a 
double-blinded, placebo-controlled randomized study to evaluate the 
chemopreventive effect of erlotinib in a high-risk group of oral IEN patients.  
We plan to recruit a total of 150 patients in 2 years with an additional 2.5 
years of follow-up.  The total study period will be 4.5 years.  Interim analyses 
will be conducted at the ends of year 2.5 and year 3.5, and the final analysis 
will be done at the end of year 4.5.  We expect a small percentage of early 
drop out or loss to follow-up (10%) due to the nature of higher compliance of 
the elevated risk groups, tolerable toxicity profile of the agent, and intense 
follow up in this population. 
 
12.2 
Analysis of Primary Endpoint 
The primary endpoint of the study is cancer-free survival defined as time from 
randomization to the development of histologically confirmed oral cancer.  All 
patients will be analyzed on an intent-to-treat basis (i.e., as randomized).  
Patients lost to follow-up due to refusal or death from other causes will be 
censored at their time of last follow-up.  The distribution of time to oral cancer 
development will be estimated by the Kaplan-Meier method.  For 
randomization purposes, eligible patients will be stratified (1) by prior oral 
cancer status (no prior oral cancer versus prior oral cancer) and (2) broadly 
by registration site (M. D. Anderson versus non-M. D. Anderson site). Within 
each stratum, Pocock-Simon dynamic allocation method will be applied to 
achieve balanced randomization with respect to potentially important factors 
including current, former and never smoking.  Patients will be randomized into 
the erlotinib arm or the placebo arm with equal probability.  Stratified log-rank 
test will be used to compare cancer-free survival among treatment groups.  
The Cox (proportional hazards) regression model will be used to incorporate 
potential prognostic factors and treatment assignment as covariates.  Details 
of the assumptions used for the sample size calculation are listed below. 
1. The study has a 2-year period to accrue 100 oral IEN/prior cancer and 50 


MDACC Protocol # 2003-0824 
Revised May 24, 2010 
Page 39 
 
IEN-alone patients, with an additional 2.5-years follow-up.  The total study 
duration is 4.5 years. 
2. The anticipated yield of LOH screening (described earlier) will be 
approximately 66% in the IEN/LOH-cancer history group and 28% in the 
IEN/LOH-alone group.  Assuming accrual rates of 60% (eligible, cancer 
history) and 45% (eligible, no cancer history), we will need to screen a 
total of 253 oral IEN patients with and 365 (accounting for year-2 accruals 
who were screened, eligible, and did not volunteer in year 1) oral IEN 
patients without a history of curatively treated oral cancer at all four 
participating centers in order to reach our total accrual goal. 
3. Time-to-oral cancer development follows an exponential distribution.  
Based on the data described earlier, 65% of the patients with IEN/LOH 
associated with curatively treated oral cancer will develop oral cancer in 
three years, and 35% of the IEN/LOH-alone patients will develop oral 
cancer in three years. 
4. Erlotinib, the active treatment, can reduce the 3-yr oral cancer rate by 
40% for the IEN/LOH-cancer history group, i.e., 3-year cancer rate will be 
reduced from 65% to 39%. This corresponds to a hazard ratio of 0.47. We 
assume the same treatment effect (hazard ratio) in the IEN/LOH-alone 
group, corresponding to the 3-yr oral cancer rate reduction from 35% to 
18%.  The parameters, lambda, for the exponential distributions are 
0.3499 (control) and 0.1648 (treatment) in IEN/LOH-cancer history 
patients and 0.1436 (control) and 0.0676 (treatment) in IEN/LOH-alone 
patients, respectively. 
5. We assume the rate of lost-to-follow up, which includes patient refusal, 
early drop out, or competing risk, etc. is 10%.  The distribution of the time 
to loss to follow-up is assumed to be uniform. 
6. Stratified log-rank test (stratify by the randomization stratification 
factors) is used to compare the cancer-free survival between the active 
and control groups. 
7. Two interim analyses are planned – one at the end of year 2.5 and 
another one at the end of year 3.5.  The final analysis will be performed at 
the end of year 4.5.  We will apply the group sequential design with the 
O’Brien-Fleming boundary to control the overall two-sided type I error rate 
to 5%.  The levels of significance for the first, second, and third tests are 
0.0005, 0.014, 0.045, respectively. 
 
Based on the above assumptions, we ran simulation studies with 10,000 
replications.  The results show that a total of 150 patients will allow us to have 
85% power with a two-sided 5% type I error rate. 
 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
13.1 
Ethical Standards and Notifications 
This trial will be conducted in compliance with the protocol, Good Clinical 
Practice (GCP), and the applicable regulatory requirements. 
 
 
13.2 
IRB Approval 
The study will be reviewed by the IRBs at M. D. Anderson Cancer Center, 
Memorial Sloan Kettering Cancer Center, Emory University, University of 
Chicago, and the University of Maryland. The protocol will also be reviewed 
by the National Cancer Institute and the FDA.  


MDACC Protocol # 2003-0824 
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Page 40 
 
 
13.3 
Patient Data Protection and Confidentiality 
Each study participant will be assigned a unique study ID number to assure 
confidentiality. 
 
Each investigator is responsible for keeping a master list of all enrolled 
patients  including their name, unique study ID number, phone number(s) and 
last known address.  
 
The patients will also be informed in the informed consent document about 
the possibility of audits by authorized representatives of the NCI, FDA, OSI 
Pharmaceuticals or study monitors, in which case a review of those parts of 
the hospital records relevant to the study may be required, with due 
consideration of the patient confidentiality.  New pathology accession 
numbers will be assigned for specimen identification versus patient hospital 
numbers.  Once assigned, these numbers are cross-referenced in a secure 
database maintained by the study statistician at M. D. Anderson Cancer 
Center. 
 
In the event of a breach of confidentiality, all investigators and the sponsors 
will be notified.  Appropriate action will be taken following consultation with 
these representatives, as well as with the involved patient(s).  Actions could 
include but will not necessarily be limited to withdrawal of the patient(s) from 
the study or recording of the patient(s) data. 
 
13.4 
Informed Consent 
The investigator is responsible for giving and documenting the patients full 
and adequate verbal and written information about the nature, purpose, 
possible risks and benefits of the study. This will include information that (a) 
this is a placebo controlled trial, (b) the study agent must be taken daily for 
the 1 year duration of the intervention, (c) they must be willing to have 
biopsies and give blood at the specified times, (d) specified follow-up visits 
with physicians and study clinics must be scheduled and kept, and (e) side 
effects and health risks may occur, as described in the consent form.  
 
The patients will be given the opportunity to refuse to participate in the study, 
under the assurance that such refusal will in no way affect their treatment at 
their study center.  The patients must also be notified that they are free to 
withdraw from the study at any time. The investigator and study research 
nurse are responsible for obtaining signed informed consent from all 
participants.  This consent form fulfills the requirements set by the Institutional 
Review Board at M. D. Anderson Cancer Center, Memorial Sloan Kettering 
Cancer Center, Emory University, the University of Chicago, and the 
University of Maryland.  It fully describes the procedures, risks, alternatives 
and potential benefits as required by FDA specifications.  A copy of the 
signed consent form will be placed in the patient’s medical record, and a 
separate copy will be maintained in the research file.  Another copy will be 
given to the patient for his or her own record. 
 
 
 
 


MDACC Protocol # 2003-0824 
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Page 41 
 
14. 
FINANCIAL SUPPORT AND DISCLOSURE 
 
14.1 
Financial Support 
The study is funded by grant P01-CA-106451 from the US National Cancer 
Institute (NCI).  OSI Pharmaceuticals will support the study by providing 
active drug and matched placebo and provide funds specifically for monitoring 
this multicenter study. The NCI and OSI Pharmaceuticals will, if requested, 
have the right to review and comment upon any manuscripts prior to 
submission for publication. 
 
14.2 
Financial Disclosure 
None of the investigators listed in this protocol have received or will receive 
financial support from OSI Pharmaceuticals.  


MDACC Protocol # 2003-0824 
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Page 42 
 
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