Conditions: Leukoplakia, Oral Benign Neoplasms
Keywords: Oral Leukoplakia Benign Neoplasms Chemoprevention Pan-cyclooxygenase (COX) inhibitor sulindac 04-099
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 63
Healthy volunteers: no

Brief summary:
The purpose of this study is to see if a drug called sulindac can prevent the development of changes in the mouth that are related to oral pre-cancer growths (oral epithelial dysplasia) or oral cancer. Sulindac is an anti-inflammatory drug that has already been tested in people with arthritis (inflammation of a joint).

This study is being done by Memorial Sloan-Kettering Cancer Center in New York, Amrita Institute of Medical Sciences and Research Center in Cochin, India, and Regional Cancer Centre (RCC) in Trivandrum, India.

Detailed description:
Oral precancerous lesions (OPL) represent a valuable model for clinical trials for tobacco related cancers. However, due to the relatively low prevalence of this condition in the United States, subject accrual to such trials is slow. Conversely, in India, the prevalence of oral leukoplakia is among the highest in the world. Indeed oral cancer, caused by exposure to tobacco smoke, alcohol and betel nut quid, is the leading cause of cancer deaths in India.

To date, there are no effective treatments documented in randomized controlled clinical trials to prevent malignant transformation of leukoplakia. However, evidence that non-steroidal anti-inflammatory drugs (NSAIDs) prevent experimental and animal head and neck cancer, and colon and breast cancer in humans lends support to the promise of NSAIDs in the chemoprevention of oral cancer.

The purpose of this protocol is to pilot a multi-center chemoprevention trial of sulindac, a pan-cyclooxygenase (COX) inhibitor, for oral leukoplakia through an international collaboration between Memorial Sloan-Kettering Cancer Center (MSKCC), New York, Regional Cancer Centre (RCC) in Trivandrum, India and the Amrita Institute of Medical Sciences (AIMS), Kerala, India. Specifically, we will conduct a 66 subject, 2-arm, double-blind, placebo-controlled randomized study of sulindac 150 mg bid to test the clinical efficacy, safety and molecular effects of sulindac against OPL and OPL tissue. Oral leukoplakia subjects will be enrolled from both RCC, AIMS and MSKCC, however, we expect that most subjects will be recruited from AIMS due to the substantially higher prevalence of this condition among the Indian compared to the US population.

MSKCC will be the coordinating center for this trial, and will thus be responsible for all aspects of clinical trial design and management. Our study team, in collaboration with the Office of Clinical Research and the Office of the Physician-in-Chief, has spent a considerable amount of time and effort in developing a comprehensive data and safety monitoring (DSM) plan.

Arms:
arm 1: sulindac arm 2: placebo

Interventions: intervention 1: sulindac intervention 2: Placebo
Intervention descriptions: intervention 1: Sulindac 150 mg po bid x 24 weeks intervention 2: Placebo bid x 24 weeks

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended:2/8/13 
 
 
 
 
 
 
A Pilot Multi-Center International Double-Blind Placebo Controlled 
Randomized Study of Sulindac, a Pan-COX Inhibitor, in Oral Premalignant 
Lesions 
THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
Jay O. Boyle, MD 
Surgery, Head and Neck 
Co-Principal Investigator(s)/Department: 
David G. Pfister, MD 
Medicine, Head and Neck 
Investigator(s)/Department: 
Jatin P. Shah, MD 
Ashok R. Shaha, MD 
Bhuvanesh Singh, MD 
Richard J. Wong, MD 
Luc Morris, MD 
Chaya S. Moskowitz, PhD 
Irene Orlow, PhD 
Nora Katabi, MD 
Victor Reuter, MD 
Nancy Y. Lee, MD 
Scott Freeswick, MS, RPh 
Pampa Roy, PhD 
Surgery, Head and Neck 
Surgery, Head and Neck 
Surgery, Head and Neck 
Surgery, Head and Neck 
Surgery, Head and Neck 
Epidemiology & Biostatistics, 
Biostat Service 
Epidemiology & Biostatistics, 
Epi.  Service 
Pathology 
Pathology 
Radiation Oncology 
Pharmacy 
Epidemiology & Biostatistics, 
Epi Service 
Consenting Professional(s)/Department: 
Jay O. Boyle, MD 
Jatin P. Shah, MD 
Ashok R. Shaha, MD 
Bhuvanesh Singh, MD 
Richard J. Wong, MD 
Luc Morris, MD 
Nancy Y. Lee, MD 
David G. Pfister, MD 
Surgery, Head and Neck 
Surgery, Head and Neck 
Surgery, Head and Neck 
Surgery, Head and Neck 
Surgery, Head and Neck 
Surgery, Head and Neck 
Radiation Oncology 
Medicine, Head and Neck 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Participating Institutions – If multicenter 
study coordinated by MSKCC: 
PI's Name 
Site's Role 
Regional Cancer Center (RCC), Trivandrum, 
India 
Paul Sebastian, MS (Master of 
Surgery) 
Data Collection 
Amrita Institute of Sciences (AIMS), Cochin, 
India 
M. Abraham Kuriakose, DDS, MD, 
PhD 
Data Analysis 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
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Amrita Institute of Sciences (AIMS), Cochin, 
India 
Kinjal Vora, MBBS, MPA 
Consultant 
Weill Medical College of Cornell University, 
New York, NY 
Andrew J. Dannenberg, MD, 
Specimen Analysis 
Mazumdar Shaw Cancer Center (MSCC) 
M. Abraham Kuriakose, DDS, MD, 
PhD and Elango. E. Murugaian, PhD 
Specimen Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................ 1 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................... 3 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 3 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................... 15 
4.2 DESIGN .................................................................................................................... 15 
4.3 INTERVENTION ..................................................................................................... 16 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ..................................................................... 16 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 18 
6.2 SUBJECT INCLUSION CRITERIA ........................................................................ 19 
6.3 SUBJECT EXCLUSION CRITERIA ....................................................................... 20 
7.0 
RECRUITMENT PLAN ................................................................................................... 21 
8.0 
PRETREATMENT EVALUATION ................................................................................ 22 
9.0 
TREATMENT/INTERVENTION PLAN ......................................................................... 25 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ......................................... 27 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................... 33 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............... 33 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 34 
14.0 
BIOSTATISTICS .............................................................................................................. 34 
15.1 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES ..................... 37 
15.2 SUBJECT REGISTRATION .................................................................................. 37 
15.3 RANDOMIZATION ............................................................................................... 38 
16.1 
DATA MANAGEMENT ISSUES ....................................................................................... 39 
16.2 QUALITY ASSURANCE ...................................................................................... 39 
16.3 DATA AND SAFETY MONITORING ................................................................. 40 
17.1 
PROTECTION OF HUMAN SUBJECTS ........................................................................ 40 
17.2 PRIVACY ............................................................................................................... 41 
17.3 SERIOUS ADVERSE EVENT (SAE) REPORTING ............................................ 41 
18.1 
INFORMED CONSENT PROCEDURES ........................................................................ 42 
18.2 RESEARCH AUTHORIZATION .......................................................................... 42 
19.0 
REFERENCE(S) ............................................................................................................... 43 
20.0 
APPENDICES .................................................................................................................. 52 
 
 
 
 
 
 
 
 
 
 
 
 
Amended:2/8/13 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Introduction 
Oral precancerous lesions (OPL) represent a valuable model for clinical trials for tobacco 
related cancers. However, due to the relatively low prevalence of this condition in the United 
States, subject accrual to such trials is slow. Conversely, in India, the prevalence of oral 
leukoplakia is among the highest in the world. Indeed oral cancer, caused by exposure to 
tobacco smoke, alcohol and betel nut quid, is the leading cause of cancer deaths in India. 
 
To date, there are no effective treatments documented in randomized controlled clinical trials 
to prevent malignant transformation of leukoplakia. However, evidence that non-steroidal 
anti-inflammatory drugs (NSAIDs) prevent experimental and animal head and neck cancer, 
and colon and breast cancer in humans lends support to the promise of NSAIDs in the 
chemoprevention of oral cancer. 
 
The purpose of this protocol is to pilot a multi-center chemoprevention trial of sulindac, a 
pan-cyclooxygenase (COX) inhibitor, for oral leukoplakia through an international 
collaboration between Memorial Sloan-Kettering Cancer Center (MSKCC), New York and 
the Amrita Institute of Medical Sciences (AIMS) and the Regional Cancer Centre (RCC), 
in Cochin and Trivandrum, India. Specifically, we will conduct a 66 subject, 2-arm, double- 
blind, placebo-controlled randomized study of sulindac 150 mg bid to test the clinical 
efficacy, safety and molecular effects of sulindac against OPL and OPL tissue. Oral 
leukoplakia subjects will be enrolled from AIMS, RCC and MSKCC, however, we expect that 
most subjects will be recruited from AIMS and RCC due to the substantially higher 
prevalence of this condition among the Indian compared to the US population. 
 
MSKCC will be the coordinating center for this trial, and will thus be responsible for all 
aspects of clinical trial design and management. Our study team, in collaboration with the 
Office of Clinical Research and the Office of the Physician-in-Chief, has spent a considerable 
amount of time and effort in developing a comprehensive data and safety monitoring (DSM) 
plan. An informal, yet critical objective of this trial is to determine the feasibility of 
conducting this multi-center trial and to further refine the operating procedures and 
DSM plan for future studies. 
 
 
Objectives 
 
Primary Objective 
 
To evaluate the efficacy of sulindac in subjects with early or advanced oral premalignant 
lesion (OPL) by both clinical response (reduction in size of all lesions) and histological 
response (change in histological grade). 
 
 
 
 
 
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Secondary Objectives 
 
To evaluate the effect of sulindac in modulating the expression of the intermediate biomarkers 
Ki67, p53 proteins and DNA ploidy after 24 weeks of treatment of study drug. 
 
To evaluate the correlation between baseline COX-2 expression or DNA ploidy with clinical 
response or biomarker modulation 
 
To evaluate the safety of chronic dosing of sulindac in this subject population 
 
To explore the relationship between genetic polymorphisms of genes involved in 
carcinogenesis and clinical or biomarker response to sulindac 
 
 
DESIGN 
 
Subjects will have a histologically suspected or confirmed index oral premalignant lesion, 
12mm or greater in size that has not been biopsied in the past 6 weeks. Subjects will be 
stratified by clinic site, and an index oral premalignant lesion will be identified and stratified 
as either: 
 
EARLY: 
presence of at least atypical cells; or mild dysplasia; or hyperplastic leukoplakia of high-risk 
sites, lateral and ventral tongue, and floor of mouth 
or 
ADVANCED: 
presence of moderate dysplasia; and/or 
presence of severe dysplasia (excluding CIS). 
 
Sixty-six subjects will be randomized either to placebo or sulindac 150 mg bid treatment 
stratified by clinic site and early or advanced lesions. 
 
While receiving study drug, subjects will have clinic visits every 4 weeks. Subjects will have 
the index lesion (or lesion area) biopsied and histologically confirmed at registration, and after 
24 weeks of treatment. The oral evaluations performed at 24 weeks will be used to determine 
final response. 
 
Biopsies and blood samples will be used for analysis of biomarkers. These include: COX-2 
mRNA (at baseline), DNA ploidy, p53 protein, Ki67 protein, and genetic polymorphisms. IHC 
for p53 and Ki67 are to be assessed at AIMS and MSKCC; samples from RCC will be sent to 
AIMS for analysis. Methodology for DNA ploidy status is currently under development. 
COX-2 levels will be measured in Dr. Dannenberg’s laboratory, at Weill Medical College of 


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Cornell University, and future genetic polymorphic analyses will be performed at MSKCC 
Molecular Epidemiology Laboratory. 
 
The efficacy of sulindac will be evaluated by the proportion of subjects that present with a CR 
or PR at 24 weeks. The study is powered to provide an 80% chance of seeing a 30% response 
rate. 
 
Adverse signs and symptoms and concurrent medications will be recorded at 4-week intervals 
while receiving study drug and at the end of the study. Safety will be assessed by comparing 
physical exams, clinical laboratory tests and adverse events. 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective 
• 
To evaluate the efficacy of sulindac in subjects with early or advanced oral premalignant 
lesion (OPL) by both clinical response (reduction in size of all lesions) and histological 
response (change in histological grade) 
 
Secondary Objectives 
 
• 
To evaluate the effect of sulindac in modulating the expression of the intermediate 
biomarkers Ki67, p53 proteins and DNA ploidy after 24 weeks of treatment of study drug 
 
• 
To evaluate the correlation between baseline COX-2 expression or DNA ploidy with 
clinical response or biomarker modulation 
 
• 
To evaluate the safety of chronic dosing of sulindac in this subject population 
 
• 
To explore the relationship between genetic polymorphisms of genes involved in 
carcinogenesis and clinical or biomarker response to sulindac 
 
3.0 
BACKGROUND AND RATIONALE 
Epidemiology of Head and Neck Cancer 
Head and neck cancers accounted for 3% of all new cancer cases and 2% of cancer deaths in 
the United States in 1999 (1). Despite multimodality treatment efforts including surgery, 
radiation therapy, and chemotherapy, the overall survival rates for head and neck cancer 
subjects have improved only modestly. (2). The main reasons for treatment failure are the 
development of second primary tumors in subjects with early stage disease (Stage I and II) 
and the development of local recurrence and metastasis for subjects with locally advanced 
disease (Stage III and IV) head and neck squamous cell carcinoma (HNSCC) (2). 


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In the Indian population to be studied, head and neck cancer accounts for 50% of all cancers 
(3). A large proportion of the population has precancerous oral leukoplakia due to the 
prevalent habits of tobacco smoking in the form of ‘bidi’ cigarettes, reverse smoking (lighted 
end in the mouth), alcohol consumption, and chronic use of betel quid (areca nut, lime, and 
tobacco) held in the buccogingival sulcus for extended periods. The ‘oral precancerous lesion 
clinic’ at AIMS, run by Dr. Kuriakose, sees 40 patients bi-monthly, while Dr. Sebastian and 
his surgical oncology group at RCC see close to 20-25 subjects who have oral premalignant 
lesions. The primary risk factors include smoking tobacco and alcohol consumption. 
 
HNSCC results from a multistep carcinogenesis process which occurs over large areas of the 
upper aerodigestive tract epithelium exposed to carcinogens. This condemned mucosa 
contains multiple transformed clones that can develop into new primary tumors at a rate of 
30% over five years. This process is called “field cancerization” (4). These patients harbor 
multifocal, metachronous, premalignant and lesions. Clinical efficacy in treating oral 
precancerous lesions may suggest efficacy of agents in preventing primary or second primary 
tobacco related cancers. 
 
Oral Premalignant Lesions (OPLs) 
Oral premalignant lesions (OPLs) are white and/or red mucosal patches in the upper 
aerodigestive tract. The histologic appearance of oral premalignancy varies from hyperplasia 
with atypical cells to severe dysplasia. 
 
The standard of care for OPLs is observation or removal. If the area is extensively involved, 
or multiplicity prohibits excision, the only alternative is close observation. The recurrence rate 
after excision of leukoplakia is 35%. Repeated surgical excisions can be associated with 
scarring and poor functional outcome. 
 
Prospective studies of subjects with OPLs revealed a significant incidence of malignant 
transformation to SCC depending primarily upon the presence of dysplasia.   In the largest 
U.S. series consisting of 257 untreated oral leukoplakia subjects, Silverman et al., determined 
the malignant transformation rate at 8 years was 17.5%, however, the rate rose to 36.4% for 
those with dysplasia (5). None of the dysplastic lesions improved spontaneously. A large 
study by Silverman of Indian workers with OPL showed similar findings (6). Pindborg 
reports hyperplastic lesions of high risk sites have increased risk of progression to cancer (99). 
 
Clinical trials of drug therapy for OPLs 
Despite many clinical trials with retinoids, the narrow therapeutic window of these agents 
does not allow their safe routine use for these lesions (7). A randomized, placebo-controlled, 
double-blind trial evaluated the efficacy of 13-cis-retinoic acid in halting or reversing the 
development of OPLs (8). A total of 46 subjects were randomized to treatment with 13-cRA 
(1-2 mg/kg/day) or placebo for three months, with six further months of follow-up. Intolerable 
conjunctivitis and hypertriglyceridemia developed in 2 subjects receiving 2 mg/kg. Among 
the 24 13-cRA subjects, 2 had complete responses, 14 had partial responses, however relapse 
occurred 2-3 months after 13-cRA therapy ended. 


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Another randomized, double-blind trial was designed to evaluate low-dose 13-cRA versus - 
carotene in maintaining remission of oral premalignancy following induction therapy with 
high-dose 13-cRA (9). At the conclusion of induction, the rate of response was 55% (36 
subjects), and the rate of stable disease was 35% (30 subjects). Of the 59 subjects included in 
the second phase, 53 were evaluable.   Of these, 22 in the 13-cRA group and 13 in the 
-carotene group responded to maintenance therapy or continued to have stable lesions (92% 
vs. 45%). 
 
The biochemoprevention study employing a combination of 13-cRA, alpha-tocopherol and 
alpha-interferon was designed to address advanced premalignant lesions of the upper 
aerodigestive tract that are resistant to single agent retinoid intervention. At 6 months, 31 
subjects were evaluable for response: 12 had a pathologic complete response, 7 partial 
response, and at 12 months, 8 complete and 7 partial responses (10). 
 
Celecoxib (marketed under the brand name of Celebrex) is a FDA approved drug for 
treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis, and for the 
reduction in the number of adenomatous colorectal polyps in FAP. Celebrex was tested for 
efficacy in the management of oral leukoplakia in a recently completed trial at MSKCC and 
MDACC (results pending). That study was initiated because of the known dramatic over 
expression of Cyclooxygenase –2 (COX-2) in head and neck cancers and leukoplakia 
compared to true normal tissue, and the known high levels of prostaglandins that may 
contribute to carcinogenesis in these subjects. Cyclooxygenase exists in two forms: a 
constitutive form (COX-1) and an inducible form (COX-2).  COX-1 is normally produced by 
a wide variety of cells throughout the body, including the stomach, platelets and kidney. 
COX-2 is associated with inflammation and pain and is increased in expression at 
inflammatory sites and in many cancers and precancers. Celecoxib is a specific inhibitor of 
the inducible form of the cyclooxygenase enzyme. Inhibition of COX-1 and COX-2 is an 
important strategy for cancer treatment and prevention trials in many organ systems. NSAIDS 
including sulindac, that inhibit COX activity are widely effective in animal models of cancer 
prevention including head and neck cancer. 
 
Sulindac 
Sulindac trademarked Clinoril by Merck, is an NSAID approved for arthritis but known to 
prevent colon polyps in humans and widely studied for cancer prevention through the NCI. 
Sulindac is a prodrug that is metabolized to two active moieties, which competitively inhibit 
COX-1 and COX –2 enzymes. It has been proven effective as a chemopreventive in several 
animal models of chemically induced cancer (11-13). It has been tested in humans for the 
prevention of colon cancer (14). The principal toxicities are the potential for upper GI 
ulceration, and platelet dysfunction, and renal toxicity. 


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Rationale for NSAIDs in chemoprevention 
Current chemoprevention strategies in several areas are focusing on developing agents that 
inhibit the activity of COX enzymes. One effect of these cancer prevention mechanisms is 
down-regulation of prostaglandin synthesis in premalignant and malignant tissue. Another 
potential mechanism by which COX contributes to carcinogenesis is by catalyzing not only 
the synthesis of prostaglandins but by activating the metabolism of carcinogens to reactive 
mutagenic electrophiles (15, 16). Increased levels of prostaglandins have been detected in 
multiple epithelial cancers, including those of head and neck origin (17). 
 
Prostaglandins are important in the post-initiation phases of tumorigenesis as they modulate 
immune surveillance by inhibiting the immune response to malignant cells, affecting cell 
proliferation and promoting angiogenesis (18, 19). Both COX-1 and COX-2, encoded by 
separate genes, catalyze the synthesis of prostaglandins. COX-1 is a constitutive enzyme with 
constant levels of expression and COX-2 is an inducible isoform encoded by an  early 
response gene that is induced by growth factors, tumor promoters, oncogenes and carcinogens 
(20-23). Overexpression of COX-2 in epithelial cells inhibits apoptosis, which increases the 
tumorigenic potential of initiated cells (18). 
 
COX catalyzes the oxidation of B[a]P-7,8-dihydrodiol to B[a]P-diolepoxide, which is a highly 
reactive and a strongly mutagenic carcinogen (24). The COX enzyme system is especially 
important in bioactivating chemicals in extrahepatic tissues, such as head and neck, where the 
P-450 mono-oxygenase system has low activity. COX converts a broad array of carcinogens 
to reactive metabolites which can form DNA adducts. Thus, several mutagenic derivatives are 
activated by COX. By analogy to the inducing effects of B[a]P on selected P-450s, benzo[a] 
pyrene upregulates COX-2 gene expression in human normal and transformed oral epithelial 
cells through increased transcription, linking COX-2 to the pathogenesis of smoking-related 
cancers, including head and neck cancer (22). 
 
Upregulated COX-2 expression was found in HNSCC (25). Mean levels of COX-2 mRNA 
were increased by 150-fold in HNSCC compared with normal oral mucosa from healthy 
volunteers, and a 50-fold increase in COX-2 mRNA in normal-appearing epithelium adjacent 
to HNSCC. IHC shows induction of COX-2 in oral leukoplakia. 
 
Sulindac has not been previously studied as a chemopreventive agent for HNSCC. A 
definitive trial of the chemopreventive efficacy of sulindac for HNSCC would require a large 
and lengthy randomized trial using an endpoint like cancer onset as the primary outcome. 
Such a study requires some knowledge of a clinically relevant effect in the population of 
interest as well as preliminary evidence that sulindac may have chemopreventive qualities and 
is worth studying further in this population. This pilot study is designed to explore if sulindac 
is worth carrying forward into a larger study and to provide the information necessary to 
design such a study. In addition, an informal objective of this study is to determine the 
feasibility of conducting a multi-center international clinical chemoprevention study among 
subjects in the US and in the high risk Indian population. By randomizing subjects, we can 
also observe whether this subject population will agree to participate in this type of study and 


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be randomized to treatment or placebo. This information is vital for assessing whether future 
studies can be carried out in collaboration with AIMS and/or RCC. 
 
Rationale for selection of Sulindac: 
As outlined above, there is extensive clinical and preclinical data suggesting a role for COX-2 
in carcinogenesis and for COX inhibitors for treatment and prevention of cancers. Selective 
COX-2 inhibitors are being extensively studied in this regard. However, in recent months, two 
reports have suggested new evidence of cardiotoxicity for these agents (94, 95) leading to 
renewed interest in pan COX inhibitors such as sulindac due to a long history of safety in the 
post marketing setting. Sulindac has been proven to reduce precancerous lesions in the human 
colon and so represents an ideal agent to test in tobacco related cancer prevention (14). 
Recently one preclinical study shows sulindac causes apoptosis in head and neck cancer cell 
lines (96) and another reports efficacy of sulindac for inhibiting precancerous markers in a 
mouse model of lung carcinogenesis (97, 98). Taken together with the continued interest in 
sulindac by the NCI, we selected sulindac as the best agent to use in this international trial. 
Sulindac represents the best balance of safety and efficacy. 
 
Rationale for the Proposed Study Population 
Oral precancers represent a valuable model for clinical trials for tobacco related cancers, but 
in the United States, accrual to these trials is slow due to the relatively low incidence of 
dysplastic oral leukoplakia in the United States. An example of accrual difficulties is a current 
multi-institutional trial of celebrex in oral precancer that has accrued just 43 subjects (half the 
goal) in 2 years accrual time at MSKCC, MDACC, and three other institutions. Because large 
randomized trials of highly promising agents are prohibitively lengthy even at the largest 
cancer centers, it is logical to look to more endemic areas of this disease, such as Kerala India, 
in which to perform these important clinical trials. 
 
Dr. Kuriakose, a US trained Head and Neck Surgeon and adjunct Professor at NYU Medical 
Center, has returned to Kerala, India to lead the Head and Neck Surgery Service at a modern 
well equipped Cancer Center, the Amrita Institute for Medical Sciences (AIMS).  Dr. Paul 
Sebastian, the Head of Surgical Oncology and Chief of the Head and Neck Service at RCC in 
Trivandrum, India has over 20 years of clinical experience and great expertise and interest in 
prevention and early detection of oral cancers. Dr. Sebastian has been at MSKCC as an 
observing surgeon from March of 2008 to May of 2008.  (please see Appendix VII. 
Description of AIMS and RCC). 
 
This provides an opportunity to establish an international clinical chemoprevention 
collaboration in this high-risk area. 
 
The primary objective of this pilot multi-center international randomized clinical trial is to 
determine clinical efficacy of sulindac (provided by NCI) for oral leukoplakia. Indeed, this 66 
subject study is powered for an 80% chance of identifying a 30% difference in response rates 
between the treatment and control arms. However, an informal yet critical objective of this 
trial is to evaluate the important feasibility questions of performing such international multi- 


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center trials. This trial will demonstrate that at AIMS and RCC, compliant subjects can be 
accrued and retained in adequate numbers, that they can be adequately screened, informed, 
and monitored for safety, and that the clinical data and specimens and biomarker data can be 
reliably gathered for analysis. With the participation and oversight of MSKCC, the trial will 
be conducted at all centers in compliance with NIH guidelines, standards for the protection of 
human subjects in clinical research, and the privacy rule. 
 
The agent sulindac has a well-known favorable safety profile helping to insure the safety of 
participants. The incidence of significant GI toxicity is low and assessable by frequent 
monitoring of symptoms, which is feasible in this trial setting. Because sulindac is a COX 
inhibitor, this trial builds on current hypotheses that these agents may be efficacious in 
tobacco related cancers and so these data are likely to advance the field. 
Clinical trials show an increased risk of cardiovascular events when COX-2 selective and 
nonselective NSAIDs are used long-term. There is no data indicating specific or significant 
cardiovascular risk when using sulindac and the overall safety profile of sulindac is excellent. 
 
Biomarker Rationale 
Tumorigenesis of the aerodigestive tract is thought to represent a multistep process leading to 
an increased risk of carcinogenesis (26-28). The carcinogen-induced damage is thought to 
accumulate with time of exposure and drive the tissue through a series of changes, which 
involve genetic alterations, dysregulation of proliferation, differentiation, and cell death, as 
well as an increased capability to invade surrounding tissue. 
 
Studies have been performed to characterize the genetic changes and their phenotypic 
consequences in tissues undergoing the tumorigenesis process, or in tumors which have 
resulted from this process. As a result, a variety of markers in the tumorigenesis process have 
been developed that can be utilized during chemoprevention trials. These markers may assess 
both risk of tumor development in a tissue at risk, as well as the effect of the chemopreventive 
intervention on the premalignant tissue. 
 
The capability to ascertain tumor risk and to measure tissue response can add significant 
power to clinical chemoprevention trials for several reasons. First, the level of tumor risk 
development from premalignant lesions, while higher than that in tissues  without 
premalignant lesions, is still low enough to require large numbers of participants. The 
characterization of markers that can identify those individuals at highest risk will serve to 
make chemoprevention trials more efficient by including only those subjects who might 
derive benefit from the trial. In addition, it could reduce the number of participants who are 
subjected to the potential side effects of the intervention and would be unlikely to derive 
benefit. 
 
The use of biomarkers gives a second source of power to a chemoprevention study by 
providing surrogate intermediate markers. In most cases, the development of cancer is a long- 
term process. Therefore, the determination of efficacy in a chemoprevention trial may require 
many years of follow-up.  This not only slows the progress of chemoprevention studies, but it 


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also limits the number of potential effective agents that can be studied. Once surrogate 
intermediate markers can be identified and validated, they can be used as short-term indicators 
of response. This would decrease the length of time necessary to evaluate responsiveness to 
intervention. In addition, the use of surrogate intermediate markers will help to characterize 
the pathobiology of response and thus provide insights into new strategies for 
chemopreventive intervention. In many cases, it is not fully understood why particular 
chemopreventive agents are effective in reversing or halting the tumorigenesis process. The 
development of biomarkers will help achieve a better understanding of how the agents work at 
the tissue level. This will then lead to new rationales for treatment. 
 
Based on this rationale the proposed trial will also incorporate the study of candidate 
intermediate biomarkers of the head and neck tumorigenesis process. As secondary 
endpoints, the modulation of several genotypic and phenotypic candidate biomarkers for the 
head and neck tumorigenesis process are targeted in an effort to define aspects of the 
tumorigenesis pathway. The biomarker candidate studies proposed are: 1) COX-2 mRNA 
expression, 2) p53 expression, 3) Proliferation status by Ki67 staining 4) DNA ploidy, a 
marker of genomic instability that is correlated with risk to progression 5) genetic 
polymorphisms of genes related to carcinogenesis and sulindac effects. 
 
COX-2 Expression 
Levels of COX-2 are increased in HNSCC as well as in normal-appearing mucosa adjacent to 
HNSCC (25), suggesting that upregulation of COX-2 expression can occur early during the 
head and neck tumorigenesis process and that down-regulation of its expression may 
accompany response to chemopreventive intervention. It will be important to  correlate 
baseline levels of COX-2 with clinical response to COX inhibitor therapy with sulindac. 
 
To analyze the expression of COX-2, a sensitive competitive RT-PCR assay has been 
developed in which the amount of COX-2 mRNA will be measured from small quantities of 
RNA. This method relies on the co-amplification in the same tube of known amounts of 
competitor DNA with COX-2 cDNA obtained after reverse transcription from total tissue 
RNA. The competitor and target use the same PCR primers but yield amplicons with a 
different size allowing their separation on a gel at the end of the reaction. 
 
p53 Expression 
Mutation of the p53 gene has been found in 40-50% of head and neck cancers and  is 
frequently associated with an increased level of p53 product in the cells. It has been found 
that p53 overexpression is a frequent occurrence in oral premalignant lesions and was 
associated with decreased response to retinoid chemoprevention and increased rates of 
progressive disease or cancer (29, 30). Although p53 overexpression in premalignant lesions 
is not always associated with p53 gene mutation, studies suggest that it might precede gene 
mutation. In relation to COX, the recent observation that wt p53 suppresses transcription of 
COX, lends support to the hypothesis that cells that carry alterations in the p53 pathway 
(which occur frequently in dysplastic oropharyngeal lesions) could express higher levels of 
COX-2 and thus provide better targets for COX inhibition compared to normal cells. P53 


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protein expression by immunohistochemistry is a well characterized assay frequently used in 
many types of clinical cancer therapeutic and prevention trials. 
 
Ki67 
Proliferative dysregulation has been a long standing identifiable characteristic of the 
tumorigenesis process and has been extensively assessed in prior chemoprevention studies. 
The proliferative fraction of cells in premalignant lesions appears to increase as tissue passes 
from normal histology to hyperplasia to dysplasia then to cancer (31). Interventions that 
reduce proliferation are likely to be clinically helpful. Ki67 protein expression measured by 
immunohistochemistry is a well characterized surrogate endpoint used frequently in 
chemoprevention trials. 
 
DNA Ploidy 
DNA ploidy is a gross marker of genetic abnormalities and has been specifically correlated 
with the risk of progression of OPL to invasive cancer. As aneuploid lesions represent the 
highest risk lesions, the efficacy of sulindac in aneuploid lesions is an important assessment. It 
has been shown in previous work that aneuploidy correlates with elevated COX-2 expression 
in oral lesions suggesting that NSAID approaches may be efficacious in these lesions. 
Obviously, if any intervention could normalize aneuploidy this would represent an important 
finding. 
 
Genetic polymorphisms: 
In addition to the above biomarkers, we propose to extract DNA from whole blood for future 
exploratory genetic analyses. Beyond the scope of this proposal, future investigations will 
examine whether polymorphisms in candidate genes that code for xenobiotic metabolizing 
enzymes in carcinogen activation and detoxification pathways (CYP1A1, GSTM1 and 
GSTMT1) modify the effect of sulindac on final response and biomarker modulation in oral 
premalignant lesions. 
 
The identification of both genetic and environmental factors that determine an individual’s 
susceptibility for the development of cancer is an important ongoing goal of molecular 
epidemiology. Most pertinent to the current proposal, susceptibility to oral cancer may be 
mediated by genetically determined differences in the activity of drug metabolizing enzymes 
involved in the detoxification and activation of carcinogens derived from tobacco smoke, 
smokeless tobacco and betel quid constituents. Thus, it is biologically plausible that within 
the current trial, an individual’s response to sulindac treatment may be modified by their 
ability to metabolically process past or ongoing carcinogenic  exposures.  Consequently, 
nested within this randomized clinical chemoprevention trial, we propose to evaluate the 
effect of sulindac treatment on OPL among subgroups of individuals characterized by 
candidate genotypes associated with higher cancer susceptibility. The following section will 
provide the rationale behind this exploratory investigation by briefly describing the main 
factors of carcinogenic exposure, the predominant enzymes that metabolize such compounds, 
the prevalence of known polymorphisms of genes that encode these enzymes, and the 
association of these polymorphisms with cancer risk. 


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The function of the most intensely studied members of the CYP and GST families, the 
prevalence and functionality of their known genetic polymorphisms, as well as their 
association with cancer risk in populations of various ethnicity’s is described. 
 
Cytochrome p450’s 
The CYP family catalyze the oxidative metabolism of most endogenous chemicals (e.g. 
hormones and fatty acids) and exogenous chemicals (e.g. polycyclic aromatic hydrocarbons, 
aromatic amines and mycotoxins) (32). CYP1A1, the most intensely studied member of this 
family, is induced by cigarette-smoke in the oral cavity of humans and by aryl hydrocarbons 
in vitro epithelial cells (33) and is thought to be responsible for the reactive oxygenated 
metabolite-mediated oxidative stress of cigarette-smoke constituents, and nitrosamines. 
Phenotyping studies have shown that the CYP1A1 exon 7 isoleucine/valine substitution 
polymorphism is associated with relevant functional differences. Importantly, the 
polymorphic amino acid change from ile/val at amino acid residue 462 of the CYP1A1 
enzyme has been shown to result in higher catalytic and mutagenic activity towards 
benzo[a]pyrene (34), 7-ethoxyresorfin (35-37) and both (R)-6- and 8-hydroxy-warfarin (37, 
38). 
 
Linkage between this polymorphism and increased lung cancer risk has been suggested in a 
recent pooled analysis of 11 international studies including a total of 1950 cases and 2617 
controls (39, 40), in Chinese (41), Japanese (42), Brazilian (43), Finnish (44) but not in 
Swedish (45) populations. Although relatively few studies have reported the frequency of the 
CYP1A1 polymorphism and its association with oral cancer risk, the first case-control study 
of the CYP1A1 polymorphism and oral cancer risk showed a prevalence of CYP1A1 exon 7 
(ile:val + val/val) genotype in white American male and female oral cancer subjects and 
controls to be 18% and 8%, respectively, resulting in a statistically significant odds ratio of 
2.5 (95% CI=1.2-5.7) (46). Subsequent studies conducted in Japan and Taiwan also found 
that individuals with the CYP1A1 exon 7 polymorphism were at increased risk for oral cancer 
and oral precancerous lesions (47, 48). A positive association between the CYP1A1 exon 7 
polymorphism and increased oral cancer risk has also been observed in the Indian population 
(Table 1). Table 1 also shows the high prevalence of the CYP1A1 exon 7 polymorphism in 
two studies of unrelated healthy individuals (49, 50). 


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Table 1. Frequency distribution of CYP1A1 genotype in the Indian population 
 
 
Reference 
Disease 
No. of 
cases 
No. of 
controls 
Ile/Val genotype 
among cases (%) 
Ile/Val genotype 
among controls (%) 
OR 
(95% CI) 
(32) 
Oral cancer 
98 
60 
CYP1A1*2 (51) 
CYP1A1*2 (17) 
5.3 
(1.0-26.3) 
(49) 
Unrelated 
- 
139 
- 
CYP1A1*2 (18) 
healthy 
individuals 
(50) 
Unrelated 
- 
883 
- 
CYP1A1*2 (21) 
- 
healthy 
individuals 
 
 
GST’s 
The GST’s are involved in the detoxification of a wide variety of active metabolites of 
tobacco carcinogens (51, 52). Specifically, GST’s are dimeric proteins that catalyze 
conjugation reactions between glutathione and diverse electrophilic compounds such as 
aromatic heterocyclic radicals and epoxides in tobacco smoke to produce a less reactive, 
water-soluble metabolite more readily excreted from the urine. GST enzymes are coded for at 
five distinct loci, known as alpha, mu, theta, pi and gamma. Two loci in particular, GSTM1 
and GSTT1 may be of relevance for susceptibility to HNSCC. 
 
The GSTM1 locus has been mapped on chromosome 1p13.3, and has been observed to be 
expressed in the squamous mucosa of the head and neck (53). Because persons with 
homozygous deletions of the GSTM1 locus have no enzymatic functional activity of the 
GSTM1 enzyme (54), these individuals potentially accumulate more DNA adducts through 
their inefficiency at excreting 7,8-diol-9,10-expoxide, the activated carcinogen of the 
polycyclic aromatic hydrocarbon benzo-[a]-pyrene in tobacco smoke (55). 
 
A recent review of case-control studies (55) indicates that the prevalence of gene variants for 
GSTM1 varies by ethnicity. Among hospital-based case-control studies conducted in the 
United States, reported frequencies of the GSTM1 deletion genotype range from 23-41% for 
persons of African descent, 32-53% for persons of Asian descent, 40-53% for those of 
Hispanic descent and 35-62% for those of European descent. Population based studies have 
reported prevalences of 48-57% for the GSTM1 deletion genotype among US Caucasians, 
while Pacific Islanders and Malaysians have reported GSTM1 deletion genotype frequencies 
of 62-100%. Other Asian populations, such as the Japanese and Chinese, also have a high 
frequency of GSTM1 deletions (48-50% and 35-63%, respectively). 


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Homozygous deletion of GSTM1 has been associated with higher risk of laryngeal, lung (56- 
64), bladder (65-67), breast (68-70)(35, 36), colon and gastrointestinal cancers (71-73)(12, 37- 
47) as well as shorter survival among lung cancer patients (74). The  epidemiological 
evidence of an association between the deletion of GSTM1 and oral cancer susceptibility is 
inconsistent. While several studies suggest the deletion of GSTM1 predisposes an individual 
to oral cancer (75-80) others do not (46, 81-86). However, studies conducted in Japan 
consistently indicate that the GSTM1 deletion genotype is associated with increased oral 
cancer risk (OR range from 1.7-2.2) (87-89). Positive associations between GSTM1 deletion 
genotype and increased oral cancer risk have also been observed in the Indian population 
(Table 2a). 
 
Table 2a. Frequency distribution of GSTM1 genotypes in the Indian population 
 
 
Reference 
Disease 
No. of 
cases 
No. of 
controls 
Deletion genotype 
among cases (%) 
Deletion genotype 
among controls (%) 
OR 
(95% CI) 
(90) 
Oral cancer 
297 
450 
GSTM1 (49) 
GSTM1 (24) 
3.2 
(2.4-4.3) 
(32) 
Oral cancer 
98 
60 
GSTM1 (49) 
GSTM1 (33) 
1.34 
(0.4-4.8) 
(91) 
Oral 
98 
82 
GSTM1 (82) 
GSTM1 (17) 
22 
leukoplakia 
(10-47) 
(49) 
Healthy 
- 
139 
- 
GSTM1 (33) 
individuals 
(50) 
Unrelated 
- 
883 
- 
GSTM1 (27) 
- 
healthy 
individual 
 
Table 2a also shows the high prevalence of the GSTM1 deletion genotype in two studies of 
unrelated healthy individuals (49, 50). 
 
The GSTT1 locus has been mapped on chromosome 22q11.2. As with homozygous deletions 
of the GSTM1 locus, individuals with homozygous deletions of GSTT1 locus have no 
enzymatic functional activity (54) against its substrates such as epoxybutanes and ethylene 
oxide derived from tobacco (92). 
 
Studies of GSTT1 null genotype in the United States demonstrate that deletion of GSTT1 is 
less common than the GSTM1 deletion genotype (55). Among those of European ancestry, 
15-31% shows no functional GSTT1 enzyme; African Americans have frequencies ranging 
from 22-29%; while those of Hispanic origin carry GSTT1 deletions of 10-12%.  Asians have 


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the highest reported GSTT1 deletion genotype. Studies report that 46-58% of Chinese, 38% 
of Malaysians, and 42-46% of Koreans have the GSTT1 null genotype. While several case- 
control studies showed an increased risk of oral cancer with the GSTT1 null genotype (OR 
ranges from 1.5-2.0) (85, 93), others have not (78, 81-83, 88). 
 
Table 2b displays the few studies reporting the frequency of GSTT1 null genotypes among the 
Indian population. 
Table 2b. Frequency distribution of GSTT1 genotypes in the Indian population 
 
 
Reference 
Disease 
No. of 
cases 
No. of 
controls 
Deletion genotype 
among cases (%) 
Deletion genotype 
among controls (%) 
OR 
(95% CI) 
(90) 
Oral cancer 
297 
450 
GSTT1 (18) 
GSTT1 (12) 
1.6 
(1.04-2.6) 
(32) 
Oral cancer 
98 
60 
GSTT1 (18) 
GSTT1 (8) 
2.5 
(0.3-21.7) 
(91) 
Oral 
98 
82 
GSTT1 (76) 
GSTT1 (22) 
11 
leukoplakia 
(5-22) 
(50) 
Unrelated 
- 
883 
- 
GSTT1 (13) 
- 
healthy 
individuals 
 
By archiving DNA extractions for future exploratory genetic analyses, we will have the 
opportunity to advance our understanding of the genetic factors that predispose this heavily 
exposed population to oral cancer. In addition, such information will allow us to identify 
commonalities and differences in oral carcinogenesis in this sample of Indian subjects relative 
to those studied in the US. If the prevalence of such genetic polymorphisms is found to be 
similar to that in the US, it may be feasible to extrapolate results obtained from the US 
studies, to that of the Indian population. Conversely, if the prevalence of such genetic 
polymorphisms is substantially different from that in the US Caucasian population, tailored 
strategies based on this knowledge will be feasible. 
Note: The molecular epidemiologic component will not be completed within the time frame 
of the proposed study. Indeed, it is likely that the emerging molecular  epidemiologic 
literature on oral cancer and precancer may stimulate further hypotheses we have not currently 
identified. Thus, upon completion of the study, we will re-evaluate and finalize our selection 
of candidate pathways and genes that will be investigated in such exploratory genetic 
analyses. 


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4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.2 
Design 
This is a pilot multi-center international double-blind, placebo-controlled randomized 
chemoprevention trial designed to determine the clinical efficacy of sulindac against OPL and 
biomarkers in OPL tissue. An informal, yet critical objective is to determine the feasibility of 
conducting such trials in India and the US. The targeted accrual is 177, with a prediction that 
66, approximately 35-40% of the total number of participants consented, will be eligible and 
will be enrolled from AIMS, RCC and MSKCC. We expect however, that most subjects will 
be recruited from AIMS and RCC due to the substantially higher prevalence of this condition 
among the Indian compared to the US population. We intend on closing to recruitment in 
March of 2014 in order that we complete accrual of 66 randomized participants. All subjects 
will be required to meet study eligibility criteria and sign consent. All procedures will be 
performed in an outpatient setting. 
 
After confirmation of the histology for the presence of either early premalignant lesions 
(hyperplasia at high risk sites, atypical hyperplasia, atypical hyperkeratosis, mild dysplasia) or 
advanced premalignant lesions (moderate or severe dysplasia), subjects will be stratified by 
clinic site and lesion grade (early or advanced lesion) subjects will be stratified by clinic site 
and for the presence of either early premalignant lesions (hyperplasia at high risk sites, 
atypical hyperplasia, atypical hyperkeratosis, mild dysplasia) or advanced premalignant 
lesions (moderate or severe dysplasia). Subjects will then be randomized to either sulindac 
150 mg bid or placebo bid for 24 weeks. At the end of 24 weeks of treatment the lesion will be 
measured for the primary assessment of clinical efficacy, and biopsied for assessment of 
secondary endpoint biomarkers. Refer to Section 14 for the statistical analysis for primary and 
secondary endpoints. The study is powered to achieve an 80% chance of identifying a 30% 
response rate. The study is planned to accrue for 24 months and to be completed in 36 months. 
 
 
6 months of treatment 
 
Study Schema 
 
 
 
 
 
 
Biopsy 
Biopsy 
 
 
 
 
Sulindac 
150 mg bid 
Early 
OPL 
Placebo 
Stratify by baseline Histology 
Randomize 
Sulindac 
150 mg bid 
Adv 
OPL 
Placebo 


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Project Timeline 
 
Months 
Tasks 
0 
4 
8 
12 
16 
20 
24 
 
 
IRB and other 
regulatory requirements 
Accrual of subjects 
Clinical trial period 
Analysis of surrogate 
biomarkers 
 
Data analysis and 
reporting 
 
 
 
 
 
 
 
4.3 Intervention 
 
Participants will be randomized to receive either sulindac 150 mg bid or placebo bid for 24 
weeks. Sulindac, a pan-COX inhibitor, trademarked Clinoril by Merck, is an NSAID 
approved for arthritis but known to prevent colon polyps in humans and widely studied for 
cancer prevention through the NCI. It has been proven effective as a chemopreventive agent 
in several animal models of chemically induced cancer (11-13), and has been tested in humans 
for the prevention of colon cancer (14). The principal toxicities are the potential for upper GI 
ulceration, and platelet dysfunction, and renal toxicity. 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Name of Drug/Agent 
Sulindac is a NSAID indene derivative designated chemically as (Z)-5-fluoro-2methyl-1-[[p- 
(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid. Sulindac is an FDA approved 
drug for treatment of signs and symptoms of arthritis in adults. 
 
Chemical Properties. 
Sulindac 
is  
(Z)-5-fluoro-2methyl-1-[[p-(methylsulfinyl)phenyl]methylene]-1H-indene-3- 
acetic acid. The empirical formula is C20H17FO3S and the molecular weight is 356.42. It is a 
yellow crystalline compound insoluble under the PH of 6. Sulindac is metabolized to the 
active sulfide by reversible reduction. It is also metabolized to the inactive sulfone by 
irreversible oxidation. 


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Dose Groups and Duration of Exposure 
Sulindac 150 mg po bid x 24 weeks 
Placebo bid x 24 weeks 
 
Packaging 
Study drug at dose levels of 150 mg bid, and placebo, will be packaged in bottles of 100 
capsules each. Subjects will receive two bottles at Week 0 and Week 12, dispensed through the 
investigational pharmacy at AIMS, RCC or MSKCC. 
 
Storage of Study Medication 
Study medication boxes will be stored in locked cabinets and distributed according to the 
treatment assignment randomly generated by the MSKCC CRDB. The pharmacist will 
maintain a dispensing log and be responsible for drug accountability. Subjects will keep the 
pills in a cool, dry place. 
 
Study Drug Administration 
Subjects will be instructed to take one capsule in the morning and one capsule in the evening. 
If a dose is missed, subjects will be instructed not to take the missed dose at the next dosing 
period. Subjects will be reminded of the importance of drug compliance during the study at 
the time of clinic visit and during telephone contacts. 
 
Supplier 
NCI will provide investigational drug supplies (sulindac 150 mg capsules or matching 
placebo) in 100 count bottles. 
 
Labeling of Clinical Supplies 
Fisher Bioservices is contracted to label and ship the study drug. Two-part labels (one fixed 
and one tear-off label) will be used for this blinded study. Upon receiving the drug shipment, 
the pharmacist at AIMS, RCC and MSKCC will remove the black sticker affixed to the tear- 
off portion of the bottle label to identify the drug contents as active or placebo. The label 
containing the lot number located below the bar code will also be removed by the pharmacist 
prior to storing the drug. For more detail please see the Pharmacy Standard Operating 
Procedures (Appendix). 
 
The fixed label will contain the following instructions: take one tablet orally twice a day as 
directed (written in English and Malayalam for AIMS and RCC subjects; in English for 
MSKCC subjects). The tear-off portion of the label (written only in English for all sites) 
identifying the drug as active or placebo will be removed from the bottle at the time of 
dispensing and attached to the DIDR 


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Dispensing 
For AIMS: The AIMS pharmacist receives a prescription from the study PI denoting the study 
IRB number and “CRDB Medical Record Number” (see the Randomization SOP for further 
details). The AIMS pharmacist matches the CRDB MRN on the prescription with the CRDB 
MRN and randomized treatment assignment contained in the email sent directly from the 
randomization coordinator at MSKCC. Once the treatment assignment is known, the AIMS 
pharmacist extracts a bottle containing 100 capsules of sulindac or placebo from the study 
inventory. The AIMS pharmacist writes the patient initials and “CRDB MRN” on the fixed 
and tear-off portions of the bottle label. The tear-off label is placed in the drug inventory log. 
The AIMS pharmacist provides the drug to Dr. Kuriakose or designated study personnel in a 
blinded fashion. All participants and study personnel, with the exception of the AIMS 
pharmacist must remain blinded to treatment assignment. Study drug is provided to the 
participant who is instructed to take one capsule twice each day. 
 
For RCC: The RCC pharmacist receives a prescription from the study PI denoting the study 
IRB number and “CRDB Medical Record Number” (see the Randomization SOP for further 
details). The RCC pharmacist matches the CRDB MRN on the prescription with the CRDB 
MRN and randomized treatment assignment contained in the email sent directly from the 
randomization coordinator at MSKCC. Once the treatment assignment is known, the RCC 
pharmacist extracts a bottle containing 100 capsules of sulindac or placebo from the study 
inventory. The RCC pharmacist writes the patient initials and “CRDB MRN” on the fixed 
and tear-off portions of the bottle label. The tear-off label is placed in the drug inventory log. 
The RCC pharmacist provides the drug to Dr. Sebastian or designated study personnel in a 
blinded fashion. All participants and study personnel, with the exception of the RCC 
pharmacist must remain blinded to treatment assignment. Study drug is provided to the 
participant who is instructed to take one capsule twice each day. 
 
 
For MSKCC: The dispensing pharmacist receives a prescription denoting the study IRB 
number and MSKCC Medical Record Number (MRN). The dispensing pharmacist 
determines the randomized treatment assignment for each new participant by searching for the 
provided MRN in the CRDB. Patient initials and “MSKCC MRN” are written on the fixed 
and tear-off portions of the bottle label. The tear-off label is placed in the drug inventory log. 
The dispensing pharmacist provides the drug to the patient, MD, RN or RSA in a blinded 
fashion. All participants and study personnel, with the exception of the dispensing 
pharmacist, must remain blinded to treatment assignment. Study drug is provided to the 
participant who is instructed to take one capsule twice each day. 
 
Drug Accountability 
A DIDR will be maintained by the pharmacist or designee. The subject will be identified by 
the subject identification number and “CRDB MRN” for AIMS and RCC, or “MSKCC MRN” 
for MSKCC subjects. Drug supplies are to be used only in accordance with this protocol and 
under the supervision of the Principal Investigator. 


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Dose Reduction 
There will be no dose reduction. Subjects will be evaluated on an individual basis. 
Rechallenge of a subject will be instituted only after the initial toxicity has been resolved to 
the satisfaction of the Principal Investigator. If toxicity recurs, the subject will be withdrawn 
from the study. 
 
Compliance 
At each clinic visit, subjects will be provided with a pill diary (see Appendix IV. Pill Diary 
and Adverse Event Form). 
 
Evaluation of Compliance 
Study drug compliance will be monitored as follows: 
1. Pill count: The RSA will perform pill counts during the 4-weekly clinic visits.   Results 
will be recorded on the 4-weekly evaluation forms. 
2. Pill diary: At each 4-weekly clinic visit, the PI or RSA at AIMS, RCC or MSKCC will 
review the pill diary that has been completed, signed and dated by each subject. The PIs 
or RSA will sign and date the pill diary. 
 
Definition of Study Drug Compliance 
Although study drug compliance will be evaluated by both methods described above, the 
definition of study drug compliance is based solely on pill count. A patient will be deemed 
compliant if the average 4-weekly pill count ≥ 80% (ie ≤ 20% capsules remain at end of each 
4-week period). If the patient has consumed less than 80% for second time, the patient will be 
terminated from the study. Counseling will be provided for first episode noncompliance. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
For this study an OPL is defined as a lesion which can include atypical hyperplasia, atypical 
hyperkeratosis, leukoplakia, and erythroplakia/erythro-leukoplakia. Histology MUST be 
confirmed by an MSKCC pathologist, for all participating sites. An OPL may be located in the 
oral cavity, oropharynx. 
 
6.2 
Subject Inclusion Criteria 
 
• 
The subject has a histologically suspected or confirmed index oral 
premalignant lesion, 12mm or greater in size that has not been biopsied in 
the past 6 weeks. Each index lesion must be either: 
 
An EARLY premalignant lesion defined to be at high risk as indicated by 
the presence of at least one of the following: atypical cells, mild dysplasia, 
or hyperplastic leukoplakia of high-risk sites, lateral and ventral tongue 
and floor of mouth 
 
OR 


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An ADVANCED premalignant lesion defined as the presence of at least 
one of the following: moderate dysplasia or severe dysplasia (excluding 
CIS) 
 
• 
The subject is > 18 years of age. 
 
• 
The subject’s life expectancy is > 12 weeks and Zubrod performance 
status is 0 or 1 (Appendix VIII). 
 
• 
The subject meets the following laboratory eligibility criteria during a time 
not to exceed 4 weeks prior to randomization. 
 
• 
Hemoglobin level above the lower limit of normal. 
• 
WBC count > 3,000/l. 
• 
Platelets count > 125,000/l. 
• 
Total bilirubin  1.5 x ULN. 
• 
AST (SGOT) and ALT (SGPT)  2.5 x ULN 
• 
BUN and serum creatinine  1.5 x ULN. 
 
• 
If the subject is female and of childbearing potential (women are 
considered not of childbearing potential if they are at least two years 
postmenopausal and/or surgically sterile), she: 
 
• 
has been using adequate contraception (abstinence, IUD, birth 
control pills, or spermicidal gel with diaphragm or condom) since 
her last menses and will use adequate contraception during the 
study, AND 
• 
is not lactating, AND 
• 
has a documented negative serum pregnancy test within 14 days 
prior to randomization. 
 
• 
If the subject is male, will use adequate contraception during the study 
 
• 
The subject’s history/use of NSAIDs, aspirin, corticosteroids meets the 
following criteria: 
 
• 
total oral/intravenous corticosteroid use has been < 14 days within 
six months of the Baseline visit, and 
• 
total  inhaled  corticosteroid  use  has  been  <  30  days  within  six 
months of the Baseline visit, and 
• 
is willing to limit aspirin use to  150 mg po per day (typical 
cardioprotective dose in India) or  81 mg po per day (typical 
cardioprotective dose in the US) for the duration of the study, and 
is willing to abstain from chronic use of all NSAIDs and COX-2 


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inhibitors for duration of study. Chronic use of NSAIDs is defined 
as a frequency of  3 times/week AND for more than a total of 14 
days a year. 
 
• 
The subject has discontinued any other chemopreventive therapy at least 3 
months prior to the Baseline visit and all toxicities have been fully 
resolved. 
 
• 
The subject has signed and dated the informed consent statement. 
 
• 
The subject is willing and able to fully participate for the duration of the 
study. 
 
• 
If applicable, the subject has been counseled on smoking cessation. 
 
 
6.3 
Subject Exclusion Criteria 
 
• 
The subject has had chemotherapy, immunotherapy, hormonal therapy 
(other than HRT for menopause), or radiation therapy within 3 weeks of 
the Baseline visit. 
 
• 
The subject has not recovered from the acute toxic effects of 
chemotherapy, immunotherapy, hormonal therapy, or radiation therapy. 
 
• 
The subject will need concurrent chemotherapy, radiotherapy, hormonal 
(other than HRT for menopause), or immunotherapy during the time of 
study. 
 
• 
The subject has a history of hypersensitivity to sulindac, COX-2 
inhibitors, NSAIDs, salicylates. 
 
• History of myocardial infarction, angina, or coronary artery disease within 
the past 6 months, or active cardiac disease. 
 
• The subject is of New York Heart Association (NYHA) Class 3 or 4 
cardiac status as defined below: 
New York Heart Association (NYHA) Classification: A Functional and Therapeutic 
Classification for Prescription of Physical Activity For Cardiac Patients. 
 
o 
Class I: patients with no limitation of activities; they suffer no symptoms from ordinary 
activities. 
 
o 
Class II: patients with slight, mild limitation of activity; they are comfortable with rest or 
with mild exertion. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 22 - 
 
 
 
o 
Class III: patients with marked limitation of activity; they are comfortable only at rest. 
 
o 
Class IV: patients who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest. 
 
• 
The subject has been diagnosed with or has been treated for esophageal, 
gastric, pyloric channel, or duodenal ulceration. 
 
• 
The subject has a history of invasive cancer within the past 1 (one) year 
(excluding non-melanoma skin cancer and in situ cervical cancer). 
 
• 
The subject has a chronic or acute renal or hepatic disorder or a significant 
bleeding disorder or any other condition which, in the Institutional 
Principal Investigator’s opinion, might preclude study participation. 
 
• 
The subject has a past history of or active inflammatory bowel disease (eg. 
Crohn’s disease or ulcerative colitis) or pancreatic disease. 
 
• 
The subject has received any investigational medication within 30 days of 
the Baseline visit or is scheduled to receive an investigational drug during 
the course of the study. 
 
• 
The subject is, in the opinion of the Institutional Principal Investigator, not 
an appropriate candidate for study participation. 
 
• 
The subject participated in the study previously and was withdrawn. 
 
Screen Failure. All subjects considered for participation and found ineligible must  be 
recorded in the Screen Failure Log. Subject confidentiality is maintained, but reason for 
exclusion is required. 
 
7.0 
RECRUITMENT PLAN 
 
In Cochin and Trivandrum, Kerala, India, where OPL and HNSCC are a significant clinical 
problem, subjects will be recruited from the AIMS Head and Neck and Dental Services and 
from the RCC the Head and Neck Surgical Service of the Surgical Oncology Department.  In 
addition, subjects from Cochin suburban communities will be recruited; the AIMS institute 
has an existing outreach program to these communities in which patients are able to be 
screened and receive care in their homes.  In New York City, New York, subjects will be 
recruited from the subject population of the Head and Neck Service, MSKCC, the 
coordinating center of this pilot multi-center international chemoprevention trial. We expect 
to enroll six eligible participants at MSKCC, 30 eligible participants at AIMS, and 30 eligible 
participants at RCC. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 23 - 
 
 
 
Upon assessment of accrual in March 2012, we predict recruitment of 66 randomized subjects 
will be completed in two years, and therefore will close the study to recruitment to accrual in 
2014. 
 
The RSA will circulate mailings to local referring professionals to solicit referrals for study 
consideration.  Subjects of all age, sex, and ethnic groups are to be considered however we 
anticipate that >90% of the study population will be Indian, due to the substantially higher 
prevalence of OPL among the Indian compared to the US population. After identification of a 
candidate OPL, and review of the inclusion and exclusion criteria, subjects will be approached 
by the consenting professional regarding candidacy for the trial. Interested subjects will 
review the subject information package, be orally counseled regarding the trial, questions 
answered and then be asked to sign the consent form. Consented subjects will then be 
registered at MSKCC.  Biopsy of the lesion will be performed to confirm histologic eligibility 
and stratification.  Subject registration at MSKCC will then be completed, to allow for 
randomization at MSKCC to occur. 
 
Subjects will not be responsible for study related expenses. AIMS and RCC subjects will be 
provided with a travel reimbursement of $7 (350 rupees) at each visit. Therefore total 
reimbursement will be $56 for the eight visits. As per MSKCC standard procedures, MSKCC 
subjects will not be reimbursed for their participation in this trial. 
 
8.1 
PRETREATMENT EVALUATION 
 
The Pretreatment Period consists of the Baseline (or Week -2) and Week 0 visits, during which 
no study medication is taken. The time that elapses between these two visits should not 
exceed eight weeks. At the Baseline visit written informed consent will be obtained for all 
potential study participants. To properly document that informed consent was obtained the 
date the informed consent was signed must be recorded in the subject’s medical record. A 
copy of the signed informed consent must be provided to the subject. 
 
8.2 
Baseline 
 
At the Baseline visit, a complete alcohol and tobacco history, inclusion/exclusion criteria, 
laboratory tests including a pregnancy test (if required), medical history and physical 
exam will be performed and recorded in the medical record. 
 
Physical  Exam  to  include:  vital  signs,  height,  weight,  blood  pressure  (sitting), 
temperature 
 
Alcohol and tobacco history will be recorded directly onto CRF. 
 
Stage One of Registration (See Section 15.1) 
 
Clinical Laboratory Tests and Other Specialized Tests and Procedures 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 24 - 
 
 
 
The following will be performed at the Baseline visit: 
 
Clinical laboratory tests to include: 
• 
CBC with differential 
• 
Platelet count 
• 
BUN 
• 
Creatinine 
• 
AST (SGOT) 
• 
ALT (SGPT) 
• 
Alkaline phosphatase 
• 
Uric acid 
• 
Glucose 
• 
Total protein 
• 
Total bilirubin 
• 
Pregnancy (if applicable) 
 
Urinalysis to include: 
• 
pH 
• 
Specific gravity 
• 
Glucose 
• 
Ketones 
• 
Protein 
• 
WBC 
• 
RBC 
• 
Bacteria 
• 
Casts 
 
Color photograph of all lesions. For monitoring purposes, the sample number will be 
recorded on each photograph. 
 
Record bi-dimensional measurements for all oral premalignant lesions. The index 
lesion will be measured before and after biopsy to ensure lesion is at least 5mm after 
biopsy. 
 
Biopsy lesion(s) 
 
The baseline biopsy of the index lesion (or lesion area) will be bisected. However, 
should it be clinically indicated to biopsy more than one lesion, ALL biopsies must be 
sent for local pathology evaluation. The pathology containing the most advanced grade 
will be used as the INDEX lesion which will be followed for purposes of this study. Only 
ONE index lesion is allowed. 
 
For AIMS subjects: One half of the baseline biopsy of the index lesion will be 
immediately placed into a labeled Eppendorf screw cap cryotube (glove handling for 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 25 - 
 
 
 
RNAase precaution) and placed in liquid nitrogen. The cryotube will then be hand- 
delivered to Dr. Elango’s laboratory where cDNA will be prepared, placed in a second 
labeled Eppendorf screw cap cryotube and stored at -80°C until transported to WMC, NY 
(See Appendix V. Shipping Instructions) for COX-2 mRNA analysis. The other portion 
of the baseline biopsy will be placed in a pre-labeled bottle of formalin and sent to the 
AIMS Department of Pathology where the H and E stained section of the biopsy will be 
evaluated and the lesion diagnosed as either early or advanced grade according to 
standard criteria. The AIMS pathologist will make photomicrographs of the biopsy and 
electronically transmit them to the Department of Pathology, MSKCC for confirmation of 
grade. The MSKCC pathologist may confer with the AIMS pathologist if there is 
disagreement. In the unlikely event the images are not satisfactory; the MSKCC 
pathologist will request overnight delivery of a single H&E slide from India. The 
MSKCC pathologist’s decision will be final. The pathology containing the most 
advanced grade will be used as the INDEX lesion which will be followed for purposes of 
this study.  Only ONE index lesion is allowed. 
 
For RCC subjects: One half of the baseline biopsy of the index lesion will be 
immediately placed into a labeled Eppendorf screw cap cryotube (glove handling for 
RNAase precaution) and placed in liquid nitrogen. The cryotube will then be stored at - 
80 degree Celsius, until shipment on dry ice once a week is made to Dr. Elango’s 
laboratory where cDNA will be prepared, placed in a second labeled Eppendorf screw 
cap cryotube and stored at -80°C until transported to WMC, NY (See Appendix V. 
Shipping Instructions) for COX-2 mRNA analysis. The other portion of the baseline 
biopsy will be placed in a pre-labeled bottle of formalin and sent to the RCC Department 
of Pathology where the H and E stained section of the biopsy will be evaluated and the 
lesion diagnosed as either early or advanced grade according to standard criteria. The 
RCC pathologist will make photomicrographs of the biopsy and electronically transmit 
them to the Department of Pathology, MSKCC for confirmation of grade. The MSKCC 
pathologist may confer with the RCC pathologist if there is disagreement. In the unlikely 
event the images are not satisfactory; the MSKCC pathologist will request overnight 
delivery of a single H&E slide from India. The MSKCC pathologist’s decision will be 
final. The pathology containing the most advanced grade will be used as the INDEX 
lesion which will be followed for purposes of this study. Only ONE index lesion is 
allowed. 
 
For MSKCC subjects: One half of the baseline biopsy of the index lesion will be 
immediately placed into a labeled Eppendorf screw cap cryotube (glove handling for 
RNAase precaution) and placed in liquid nitrogen. The cryotube will then be hand- 
delivered to Dr. Dannenberg’s laboratory where cDNA will be prepared, placed in a 
second labeled Eppendorf screw cap cryotube and stored at -80°C until COX-2 mRNA 
analysis. The other portion of the baseline biopsy will be sent to the MSKCC 
Department of Pathology for routine histology evaluation. As for the AIMS and RCC 
subjects described above, the pathology containing the most advanced grade will be used 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 26 - 
 
 
 
as the INDEX lesion which will be followed for purposes of this study. Only ONE index 
lesion is allowed. 
 
The MSKCC pathologist will electronically transmit the pathology confirmation for 
AIMS, RCC, and MSKCC subjects to the MSKCC RSA who will document this is in 
Part Two of the eligibility form and submit to the PPA to complete the second phase of 
registration. Once the registration process with the PPA system has been completed, 
randomization will occur. 
 
Record concomitant medications (any use of a nicotine supplement, ie. patch or gum, 
herbal supplements and vitamins are considered a medication and should be recorded). 
 
Record adverse signs and symptoms. 
 
Tissue banking blood: Collect one 5 mL lavender top tube of blood 
 
For AIMS subjects: Blood will be hand-delivered to Dr. Elango’s laboratory and 
aliquoted into 3-4 labeled Eppendorf screw cap cryotubes and stored at -80°C until 
transported to MSKCC, NY (See Appendix V. Shipping Instructions) for future 
genotyping analysis. 
 
For RCC subjects: Blood will be aliquoted into 3-4 labeled Eppendorf screw cap 
cryotubes and stored at -80°C and will be sent in batches, once a week to Dr. Elango’s 
laboratory for future transport to MSKCC, NY (See Appendix V. Shipping Instructions) 
for future genotyping analysis. 
 
For MSKCC subjects: The RSA will email members of the Molecular Epidemiology 
Laboratory when blood will be collected for a study participant (denote study ID number) 
and Protocol #04-099. Once the blood is collected, the specimen will be hand-delivered 
to one of the lab members or deposited in the drop box outside the Molecular 
Epidemiology Lab (Schwartz 732). Blood will be aliquoted into 3-4 labeled Eppendorf 
screw cap cryotubes and stored at -80°C for future genotyping analysis. Cryotubes will 
be labeled with the prefix SUL and the four digit sample number. 
 
Smoking and tobacco cessation counseling provided. 
 
8.3 
Admission of Subjects 
 
The following procedures will occur at the Week 0 visit: 
 
Documentation of smoking cessation counseling completion must be recorded in 
subject’s medical record. 
 
Pregnancy test: If not already completed 14 days prior to Week 0 visit, order STAT for 
results to be available prior to randomization. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 27 - 
 
 
 
Record any new interim concomitant medications 
Stage Two of Registration (See Section 15.1) 
Randomization (See Section 15.2) 
Dispense Study Medication: 
See Section 5 and the Pharmacy Standard Operating 
Procedures. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 28 - 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
SCHEMA  
Study schema for individual subjects 
 
 
 
 
 
Tasks 
 
Physical Examination 
Risk profile evaluation 
Photography & lesion measurement 
1st stage registration 
Blood collection 
Biopsy 
 
Tobacco cessation counseling 
Clinical Laboratory tests 
2nd stage registration & randomization 
 
Dispense drug 
 
Record adverse event 
Assess pill compliance * 
 
* Review pill diary and determine compliance using pill count (>= 80%) 
Monthly follow-up phone calls will also be performed at Weeks 2, 6, 10, 14, 18 and 22 
Weeks +/-1 
-2 
0 
4 
8 
12 
16 
20 
24 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 29 - 
 
 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
 
Subject Status and Dosing Schedule 
Once the subject is randomized they should begin their first dose of study medication by the 
subsequent morning. Each subject will be instructed to continue taking the dispensed study 
medication twice a day for the duration of the 24 week Treatment Period. 
 
Procedures and Observations 
Study Medication Administration 
The subject will return for visits at Weeks 4, 8, 12, 16, 20 and 24 with their previously 
dispensed study medication bottle, pill diary and remaining pills. 
Record Concurrent Medication 
 
Compliance 
 
Subject compliance is an important aspect of clinical trials. It is well documented that 
subjects recruited to studies performed in India recognize that study participation can offer 
access to quality health care and medications that may not be otherwise affordable. As a 
result, subjects exhibit a high level of compliance and motivation to attend all required study 
visits and ingest study drug as per protocol. Importantly, an independent study by a global 
Clinical Research Organization (CRO) concluded that India has one of the best subject return 
rates and compliance to clinical trial protocols in the world (Applied Clinical Trials, 
February 2003). 
 
Subject compliance will be assessed/encouraged using three methods: 
 
1. 
Pill diary 
2. 
Pill count 
3. 
Four-weekly phone calls (approximately 2 weeks after each clinic visit) 
 
1. Patients will be provided and instructed on the use of a pill diary (See Appendix IV) 
that will be completed daily, signed and dated by the patient. At 4-weekly clinic 
visits, research personnel will monitor the patient’s compliance, sign and date the pill 
diary. Signed and dated pill diaries collected in India will be immediately faxed to 
MSKCC for review and filing. In addition, a copy of the pill diary will be sent to 
MSKCC for monitoring and auditing, in batches as appropriate. 
 
2. At each clinic visit, patients will return any unused study medication and the study 
medication bottle to the investigators, who will conduct a pill count. If the patient has 
consumed less than 80% for the second time, the patient will be terminated from the 
study. Counseling will be provided for first episode noncompliance. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 30 - 
 
 
 
3. Four-weekly phone calls: patients will be contacted by research personnel 
approximately two weeks after each 4-weekly clinic visit. Patients will be encouraged 
to maintain compliance and be asked about any adverse effects or concerns they might 
have. It is important to note that our Indian collaborators have confirmed that most of 
their patients can be accessed through telephone - most directly in their homes, 
although some may need to be contacted through local telephone offices. Our 
collaborators assure us that follow up through telephone is certainly possible. 
Below is the outline of the schedule of events that will take place during the Treatment Period. 
Treatment Period 4 Weeks (1 Week) 
Physical exam 
Record concomitant medication. 
Record adverse signs and symptoms. 
Record in subject’s medical record. 
Pill  diary  and  pill  count  compliance  assessment.  Verbal  counseling  for  less  than  80% 
compliance. 
Tobacco cessation counseling 
 
Treatment Period 8 Weeks (1 Week) 
Physical exam. 
Record concomitant medication. 
Record adverse signs and symptoms. 
Pill diary and pill count compliance assessment. If less than 80% for second time, terminate 
from the study. Counseling for first episode noncompliance. 
Tobacco cessation counseling 
 
Treatment Period 12 Weeks (-1 Week or +2 Weeks) 
Physical exam. 
Record concomitant medication. 
Record adverse signs and symptoms. 
Pill diary and pill count compliance assessment 
Dispense drug for 12 weeks of treatment 
Tobacco cessation counseling 
 
Treatment Period 16 Weeks (1 Week) 
Physical exam 
Record concomitant medication. 
Record adverse signs and symptoms. 
Pill diary and pill count compliance assessment 
Tobacco cessation counseling 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
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Treatment Period 20 Weeks (1 Week) 
Physical exam 
Record concomitant medication. 
Record adverse signs and symptoms. 
Pill diary and pill count compliance assessment 
Tobacco cessation counseling 
 
Treatment Period 24 Weeks (-1 Week or +2 Weeks) 
Physical exam to include: vital signs, weight, blood pressure (sitting), temperature 
Color photograph all lesions prior to biopsy of index lesion. 
Provide bi-dimensional measurements for all lesions (if possible). 
Pill diary and pill count compliance assessment 
Biopsy index lesion. 
Do not bisect tissue for COX-2 mRNA analysis (Baseline Only). 
See Page 31 for Standard Biopsy Procedures. 
Should it be clinically necessary to biopsy any additional lesions, ALL biopsies must be 
sent for local pathology evaluation. 
Send specimen for local pathology evaluation. 
Laboratory to include: 
• CBC with differential 
• Platelet count 
• BUN 
• Creatinine 
• AST (SGOT) 
• ALT (SGPT) 
• Alkaline phosphatase 
• Uric acid 
• Glucose 
• Total protein 
• Total bilirubin 
• Urinalysis to include: 
• pH 
• Specific gravity 
• Glucose 
• Ketones 
• Protein 
• WBC 
• RBC 
• Bacteria 
• Casts 
Record all concomitant medications. 
Record all adverse signs and symptoms. 
Pill diary and pill count compliance assessment 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 32 - 
 
 
 
Tobacco cessation counseling 
 
Withdrawal of a Subject Prior to Study Completion 
Every effort will be made by the Principal Investigator to keep the subject in the study; 
however, should the subject decide to withdraw, all efforts will be made to complete and 
report the observations as thoroughly as possible. Data will include a complete final 
evaluation at the time of the subject’s withdrawal with an explanation of why the subject is 
terminated from treatment. 
 
If, for any reason, a subject withdraws before they have completed the study, the reason for 
withdrawal must be entered on the CRF. 
 
Study Procedures 
 
Measurement of lesions (Baseline and Week 24) 
Obtain the bi-dimensional measurements for all the oral premalignant lesion(s) and record on 
CRF.  For example: 
Lesion #1   2 mm width x 3 mm length = 6 mm2 (product) 
Lesion #2 1 mm width x 3 mm length = 3 mm2 (product) 
Sum of products = 9 mm2 (6 mm2 + 3 mm2) 
The pre-biopsy measurement of the index lesion should be recorded on the appropriate Week 
24 Oral Evaluation CRF. 
 
Color Photographs of All Lesions 
Color photographs or slides (per institutional standards) will be obtained for all lesions 
primarily for the documentation of clinical response. 
 
Standard Biopsy Procedures 
Note: Only the Baseline biopsy specimens will be bisected. 
Local anesthetic: at the discretion of the surgeon, topical application of 20% benzocaine, 
and/or injection of 1 or 2% lidocaine with or without 1:100,000 epinephrine or 3% 
mepivacaine without epinephrine. 
 
Incisional biopsy (4 mm punch) of the oral leukoplakia or erythroplakia lesion: using a Baker 
4 mm punch, the center or the clinically most suspicious area of the lesion is biopsied with a 
twisting motion. The circular punched out tissue is grasped gently with fine toothed forceps 
and excised just deep to the submucosa with the #15 scalpel. Care is taken to avoid collecting 
significant amounts of fat or muscle and to avoid crushing the specimen. 
 
The Baseline sample is placed mucosa side down on a clean hard surface such as a piece of 
wax paper and immediately bisected with a scalpel. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
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Amended: 2/8/13 
- 33 - 
 
 
 
For AIMS subjects: One half of the baseline biopsy of the index lesion will be immediately 
placed into a labeled Eppendorf screw cap cryotube (glove handling for RNAase precaution) 
and placed in liquid nitrogen. The cryotube will then be hand-delivered to Dr. Elango’s 
laboratory where cDNA will be prepared, placed in a second labeled Eppendorf screw cap 
cryotube and stored at -80°C until transported to WMC, NY (See Appendix V. Shipping 
Instructions) for COX-2 mRNA analysis. The other portion of the baseline biopsy will be 
placed in a pre-labeled bottle of formalin and sent to the AIMS Department of Pathology 
where the H and E stained section of the biopsy will be evaluated and the lesion diagnosed as 
either early or advanced grade according to standard criteria. The AIMS pathologist will 
make two photomicrographs of the biopsy and electronically transmit them to the Department 
of Pathology, MSKCC for confirmation of grade. The MSKCC pathologist may confer with 
the AIMS pathologist if there is disagreement. In the unlikely event the images are not 
satisfactory; the MSKCC pathologist will request overnight delivery of a single H&E slide 
from India. The MSKCC pathologist’s decision will be final. The pathology containing the 
most advanced grade will be used as the INDEX lesion which will be followed for purposes 
of this study.  Only ONE index lesion is allowed. 
 
For RCC subjects: One half of the baseline biopsy of the index lesion will be immediately 
placed into a labeled Eppendorf screw cap cryotube (glove handling for RNAase precaution), 
snap-frozen in liquid nitrogen, and stored at -80°C. Weekly dry ice shipment of biopsies will 
be made to Dr. Elango’s lab at AIMS and stored -80°C until transported to WMC, NY (See 
Appendix V. Shipping Instructions) for COX-2 mRNA analysis. The other portion of the 
baseline biopsy will be placed in a pre-labeled bottle of formalin and sent to the AIMS 
Department of Pathology where the H and E stained section of the biopsy will be evaluated 
and the lesion diagnosed as either early or advanced grade according to standard criteria. The 
AIMS pathologist will make two photomicrographs of the biopsy and electronically transmit 
them to the Department of Pathology, MSKCC for confirmation of grade. The MSKCC 
pathologist may confer with the AIMS pathologist if there is disagreement. In the unlikely 
event the images are not satisfactory; the MSKCC pathologist will request overnight delivery 
of a single H&E slide from India. The MSKCC pathologist’s decision will be final. The 
pathology containing the most advanced grade will be used as the INDEX lesion which will 
be followed for purposes of this study. Only ONE index lesion is allowed. 
 
For MSKCC subjects: One half of the baseline biopsy of the index lesion will be immediately 
placed into a labeled Eppendorf screw cap cryotube (glove handling for RNAase precaution) 
and placed in liquid nitrogen. The cryotube will then be hand-delivered to Dr. Dannenberg’s 
laboratory where cDNA will be prepared, placed in a second labeled Eppendorf screw cap 
cryotube and stored at -80°C until analyzed for COX-2 mRNA. The other portion of the 
baseline biopsy will be sent to the MSKCC Department of Pathology for routine histology 
evaluation. As for the AIMS subjects described above, the pathology containing the most 
advanced grade will be used as the INDEX lesion which will be followed for purposes of this 
study.  Only ONE index lesion is allowed. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 34 - 
 
 
 
For week 24 biopsies the entire specimen is placed in formalin and sent to pathology for 
histologic evaluation. 
 
Hemostasis is achieved by direct pressure, silver nitrate, or suture. 
 
Subjects are provided with oral wound care instructions: 4-6 times daily local rinsing with 
saline and standard post surgical instructions including notification of consulting professional 
for heavy bleeding, severe pain, or fever. 
 
For analgesia, subjects will be told to take acetaminophen 650 mg po qid PRN. 


 
 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
 
 
 
IRB#: 04-099A(18) 
 
 
 
 
 
Test Type 
Time 1 
Non-Billable 
Research 
Charges 
Time 2 
Non-Billable 
Research 
Charges 
Time 3 
Non-Billable 
Research 
Charges 
Transoral 
biopsy of 
index pre- 
malignant 
lesion 
Intial 
clinic visit 
None 
Week 24 
clinic visit 
MSKCC pts: 
10 bx @ $400 
= $4,000 
MSKCC pts: 
10 bx @ $400 
= $4,000 
Blood and 
Urine 
Clinical 
Laboratory 
Tests 
Intial 
clinic visit 
None 
Week 24 
clinic visit 
MSKCC pts: 
10 pt @ $300 
= $3,000 
 
 
 
 
 
 
 
 
 
Amended: 2/8/13 
 
- 35 - 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 36 - 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
This agent has been used extensively in humans with an excellent safety profile. All subjects 
will be closely monitored for signs and symptoms of toxicity. Toxicities will be reported 
immediately as outlined in the DSM plan. Toxicities will be graded according to the National 
Cancer Institute Common Toxicity Criteria. 
 
The most frequent adverse reactions occurring with sulindac are GI including pain in 10%, 
dyspepsia, nausea with or without vomiting, diarrhea, constipation, flatulence, and cramps. 
Rash, Dizziness, tinnitus, and edema can occur in 1% of subjects. Less than 1% of subjects 
may have GI ulceration, jaundice, hepatitis, biliary stones, skin reactions, CHF, 
thrombocytopenia, hematuria, hyperkalemia, vertigo, depression, or epistaxis. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Clinical Response (at Week 24) 
Complete Response (CR): Disappearance of all evidence of the lesions. 
Partial  Response  (PR): 
50%  or  greater  decrease  in  the  product  of  the  perpendicular 
diameters of the index lesion.  No lesion may increase in size and no new lesion may appear. 
No Change (NC):  No change in the size of the lesion(s) and no new lesions appearing. 
Progressive Disease (PD): Any increase > 25% in the product of the perpendicular diameters 
of the index lesion or in the estimated size of non-measurable lesions or the appearance of an 
unequivocal new lesion or progression to invasive carcinoma. 
 
Histologic Response (at Week 24): 
Complete Response (CR): Complete reversal of dysplasia to normal epithelium in index 
lesion and all other premalignant lesions. 
Partial Response (PR): Improvement of the degree of dysplasia in the selected premalignant 
index lesion from advanced to early or from early to normal epithelium with no change in 
non-index lesions. 
No Change (NC): No change in the degree of dysplasia in the selected lesion. 
Progressive Disease (PD): Any increase in the severity of grade of histology or progression 
to a carcinoma in the premalignant index lesion. 
 
Definition of Final Response: 
To account for possible discordance between clinical and histologic responses the following 
definitions of final response will be used, where CR=Complete response, PR=Partial 
response, NC=No Change, and PD=Progression of disease: 
Baseline EARLY 
premalignant lesion 
Clinical 
CR 
PR 
NC 
PD 
Histological 
CR 
CR 
PR 
PR 
PD 
PR 
PR 
PR 
NC 
PD 
NC 
PR 
PR 
NC 
PD 
PD 
PD 
PD 
PD 
PD 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 37 - 
 
 
 
 
Baseline ADVANCED 
Premalignant lesion 
Clinical 
CR 
PR 
NC 
PD 
Histological 
CR 
CR 
PR 
PR 
PD 
PR 
PR 
PR 
PR 
PD 
NC 
PR 
NC 
NC 
PD 
PD 
PD 
PD 
PD 
PD 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the subject develops progressive disease he/she will be taken off study and 
referred for alternative therapy. 
 
If at any time the subject develops unacceptable toxicity he/she will be removed from study. 
 
If at any time the subject is found to be ineligible for the protocol as designated in the section 
on Criteria for Subject Eligibility (i.e., a change in diagnosis), the subject will be removed 
from the study. 
 
Subjects will also be immediately discontinued from this study for any of the following 
reasons: 
Subject fails to adhere to the conditions outlined within the Schedule of Observations and 
Procedures. This could include failure of the subject to report for scheduled examinations, 
treatments, biopsy procedures or the use of excluded medication. 
Development of an invasive or progressive disease. Invasive carcinoma discovered at any 
time during study will be considered progressive disease (PD) and will result in removal from 
the study and referral for appropriate treatment. 
Any new lesion (other than the index lesion) that, in the opinion of the Investigator, warrants a 
biopsy for histologic review. 
The development of an AE with a grade 3 or 4 toxicity. 
Intercurrent illness necessitating premature termination. 
Subject withdraws consent. 
At the Principal Investigators’ discretion, the subject is removed from the study. 
Serious adverse event thought to be related to study drug. 


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14.0 
BIOSTATISTICS 
Sample Size Justification 
This is a pilot multi-center international double-blind, placebo-controlled randomized study of 
sulindac, a pan-COX inhibitor, in subjects with oral premalignant lesions treated at AIMS and 
RCC, India and MSKCC, NY. Sixty six subjects will be randomized to receive either sulindac 
or placebo for 24 weeks. 
 
The primary objective of this study is to evaluate and compare the final response rates (CR or 
PR based on clinical and histological criteria evaluated at Week 24) in the sulindac and 
placebo arms. As this is a pilot study, we do not have preliminary information on the 
expected response rate in the placebo arm of this high risk population in India, nor on what 
magnitude of difference in response rates we might expect to see between the two arms. 
Based on clinical experience with similar subjects in the USA we expect the response rate in 
the placebo arm will be approximately 4%. After accounting for a 10% dropout rate, with 33 
subjects in each arm we will be able to detect a difference of 30% between response rates in 
the two arms with 80% power and a significance level of .05. This study will be used to 
decide whether sulindac is worth studying further as a chemopreventive agent for HNSCC and 
will provide preliminary information that is necessary to design a more definitive 
chemoprevention trial. 
 
Analysis of Efficacy Endpoints 
 
Primary Efficacy 
 
The primary efficacy endpoint for this study is the percentage of subjects with CR or PR 
based on the final response evaluation at Week 24. The estimates of the percentages in each 
arm will be given together with 95% confidence intervals. The percentages will be formally 
compared using the Mantel-Hantel statistic stratifying on early/advanced premalignant lesions 
in an intent-to-treat analysis. Baseline demographic information and other potential prognostic 
factors will be explored using generalized linear models. 
 
Secondary Efficacy 
 
Response rates in the early and advanced premalignant subpopulations will be studied 
descriptively by estimating the percentages and their confidence intervals. Separate 
descriptive analyses will be done using clinical response and histological response as 
endpoints and proceeding as described above for the primary efficacy endpoint. Descriptive 
analyses will also assess the possible correlation between the clinical and histological 
response. 


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Analysis of Biomarkers 
 
Descriptive statistics will be used to assess the effects of sulindac on modulation of the 
biomarkers. Correlations among the biomarkers and between the biomarkers and response 
rate will be evaluated by both tabular and graphical form. The joint effects of biomarker 
expression on response status may be explored through the use of classification and regression 
trees such as CART or logistic regression. 
 
Analysis of Safety Endpoints 
 
All adverse events will be descriptively summarized. These analyses will consist of displays 
of the distribution by treatment group and disease category of the numbers of subjects 
reporting at least one episode of a specific adverse event (incidence table), the total number of 
episodes for each event reported (frequency table), and the severity and attribution to study 
drug of each episode reported (severity and attribution table). 
 
Listings of adverse events by subjects and by event will include the time to onset, the duration 
of each event, and the Principal Investigator’s opinion of the relationship of the event to study 
medication, whether it was a serious event, and whether it caused withdrawal. 
 
Adverse events will be coded using the World Health Organization (WHO) dictionary. 
Pearson’s chi-square will be used to test the association of treatment and overall incidence 
within each preferred term and body system. The proportion of subjects withdrawn due to 
adverse events will also be compared. 
 
At Week 24, clinical laboratory data for each treatment will be summarized for change from 
Pretreatment to Posttreatment visits. Incidence of clinically significant laboratory test results 
will be compared between treatment groups. Each laboratory value will be examined 
descriptively. 
 
Shifts in laboratory test values will be compared among treatments in terms of numbers of 
subjects showing an increase, decrease, and no change, with respect to the normal range, 
using a chi-square test. Changes from Baseline (calculated as the value at Week 24 minus the 
Baseline value) will also be compared. 
 
Laboratory data obtained any time after the first dose of study medication will not be used as 
Baseline data. Similarly, laboratory data that are obtained more than seven days after the last 
dose of study medication will be excluded from the shift table analyses. 
 
Changes in weight and vital signs from Pretreatment to Post-treatment will be calculated and 
compared across treatment groups using a t-test or a Wilcoxon rank-sum test. 


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The percentage of subjects showing changes from Baseline in the laboratory tests defined 
below will be compared between treatment groups: 
 
SGOT (AST) and SGPT (ALT): 
> 3 x ULN (upper limits of normal value) 
Alkaline Phosphatase: 
> 1.25 x ULN 
Total Bilirubin: 
> 1.5 x ULN 
Creatinine: 
> 1.3 x ULN 
BUN: 
> 2.0 x ULN 
Hematocrit: 
a decrease > 5 percent points (relative to subject’s Baseline value) 
Hemoglobin: 
a decrease > 2 grams/dl (relative to subject’s Baseline value) 
White Blood Cells: 
 
< 3000/ul 
Platelets: 
< 100,000/ul 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.2 Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735- 
0003. Registrations can be phoned in or faxed. The completed signature page of the written 
consent/verbal script and a completed Eligibility Checklist must be faxed to PPR. 
 
Stage two: 
Clinical Laboratory Test Results: 
For MSKCC subjects: the RSA at MSKCC will obtain the results of the clinical laboratory 
tests from the subject’s electronic medical record. The RSA will record the values on the 
CRF and Part Two of the eligibility form. The completed eligibility form will be faxed to the 
PPR at MSKCC once the pathology result from the baseline biopsy of the oral premalignant 
lesion is known.  A re-consent is required if registration to part 2 exceeds the 30 day limit. 
 
 
 
 
 
Pathology Results: 


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The MSKCC pathologist will electronically submit the pathology of the baseline biopsy from 
the index lesion for subjects from all sites to the RSA at MSKCC. The RSA will document 
the histology in Part Two of the eligibility form and submit the completed eligibility form to 
the PPR to complete the second phase of registration. Once the registration process with the 
PPR system has been completed, randomization will occur. 
 
15.1.1 For Participating Sites: 
 
Central registration for this study will take place at Memorial Sloan Kettering Cancer Center 
(MSKCC). 
 
To complete registration and enroll a participant from another institution, the study staff at that 
site must contact the designated research staff at MSKCC to notify him/her of the participant 
registration. The site staff then needs to fax registration/eligibility documents to the Department 
of Surgery at MSKCC at 212-557-0495 
 
Part 1 Registration 
The following documents must be sent for each enrollment within 24 hours of the informed 
consent form being signed: 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and signed HIPAA Authorization form 
• Supporting source documentation for eligibility questions (laboratory results, pathology 
report, radiology reports, MD notes, physical exam sheets, medical history, prior treatment 
records, and EKG report). 
 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct an 
interim review of all documents.  At Part 1 registration, subject will be registered as PENDING 
until clinical laboratory and pathology reports are received within 30 days of the consent. 
 
Part 2 Registration 
Clinical Laboratory Test Results: 
The RSA at AIMS and RCC will obtain the results of the clinical laboratory tests from 
their respective clinical laboratories.  The RSA will record these values on the CRF and 
Part Two of the eligibility form. The eligibility form will be faxed to the RSA at 
MSKCC (011-212-557-0495) who will then submit it to PPR at MSKCC once the 
Pathology result from the baseline biopsy of the oral premalignant lesion is known.  The 
fully completed eligibility checklist, source documentation for both laboratory and 
pathology results, and MSKCC pathologist e-mail confirmation of histology must be 
faxed to the PPR for part 2 registration within 30 days of initial registration. A re- 
consent is required if registration to part 2 exceeds the 30 day limit. 
 
 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in good 
standing with MSKCC, the MSKCC research staff will send the completed registration 


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documents to the MSKCC Protocol Participant Registration (PPR) Office to be enrolled as stated 
in section 15.1. The participant will be registered. 
 
Once eligibility has been established and the participant is registered, the participant will be 
assigned an MSKCC Clinical Research Database (CRDB) number (protocol participant number). 
This number is unique to the participant and must be written on all data and correspondence for 
the participant. This protocol participant number will be relayed back to study staff at the 
registering site via e-mail and will serve as the enrollment confirmation. 
 
15.2  Randomization 
 
On the completion of the second stage of registration, the CRDB automatically randomizes 
the participant to sulindac or placebo. 
For AIMS and RCC: 
The MSKCC RSA sends an email message to the randomization coordinator at MSKCC 
informing her that the second-stage of registration is complete. The participant’s name, study 
ID and “CRDB MRN” are provided to the randomization coordinator who accesses the CRDB 
to identify the treatment assignment for the new participant. The randomization coordinator 
sends a secure email message directly to the pharmacist at AIMS or RCC. The message 
contains the participant’s name, study ID, “CRDB MRN” and treatment assignment. The 
AIMS or RCC pharmacist sends a reply email message to the randomization coordinator to 
confirm the treatment assignment. The email messages are archived and a paper trail is 
maintained. 
 
For MSKCC: 
The MSKCC pharmacist accesses the CRDB to identify the treatment assignment for the new 
participant by matching the “MSKCC MRN” on the prescription, with the MRN stored in the 
CRDB.  Drug is dispensed by the MSKCC pharmacist according to the Pharmacy. 
 
 
16.1 
DATA MANAGEMENT ISSUES 
MSKCC will be the coordinating center for this trial, and will thus be responsible for all 
aspects of data management. Our study team, in collaboration with the Office of Clinical 
Research and the Office of the Physician-in-Chief, has spent a considerable amount of 
time and effort in developing a comprehensive data management plan (see Appendix VI. 
Data and Safety Monitoring Plan). 
 
At least one Research Study Assistant (RSA) will be assigned to the study at each site. The 
responsibilities of the RSA includes project compliance, data collection, abstraction and entry, 
data reporting, regulatory monitoring, problem resolution and prioritization, and coordination 
of the activities of the protocol study team. All data collected for this study will be entered 
into a secure database. Source documentation will be available to support the computerized 
patient record. 


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16.1.1 Data and Source Documentation for Participating Sites 
Data 
 
Standardized Case Report Forms (CRFs), directions for use and sign off requirements have been 
generated for this study. Blank case report forms will be sent to the study staff at each participating site 
for use. The participating Site PI is responsible for ensuring these forms are completed accurately, 
legibly and in a timely manner. 
 
Source Documentation 
 
Source documentation refers to original records of observations, clinical findings and evaluations that 
are subsequently recorded as data. Source documentation should be consistent with data entered into 
CRFs. Relevant source documentation to be submitted throughout the study includes: 
o Baseline measures to assess pre–protocol disease status (eg. Physical exam, oral cavity 
exam and lesion measurements, histology of lesion biopsy, blood chemistry and 
hematology) 
o Treatment records 
o Grade 3-5 toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 
 
16.1.2 Data and Source Documentation Submission for Participating Sites 
 
Participating sites should fax or e-mail CRFs and source documentation to MSKCC to the contact 
provided below.  Submissions should include a cover page listing all CRFs enclosed per participant. 
 
FAX: 212-557-0495 to the attention of 04-099 Research Staff 
 
OR 
 
EMAIL: Lasha Clarke clarkel@mskcc.org 
 
MAILING ADDRESS: 
Lasha Clarke 
633 3rd Ave, Floor 15 
New York, NY 10017 
 
Participating sites are required to keep copies of each form that is sent via postal mail. 
 
 
 
 
 
 
16.1.3 Data and Source Documentation Submission Timelines for Participating Sites 
 
Data and source documentation to support data should be transmitted to MSKCC according to 
chart below: 


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Baseline 
Weeks 4, 8, 12, 16, and 20 
Adverse Event 
Week 24 end of study/ Off 
Study 
SUBMISSION SCHEDULE 
 
Source Documentation 
Within 24 hours 
(see section 15.1.1) 
within 14 days of visit 
Within 3 days of event 
(see section 17.2.1); 
updates to be submitted as 
available 
Within 14 days of visit 
CRFs 
Within 7 days of 
visit 
Required Forms 
 
Subject Enrollment Form 
X 
X 
 
Subject Randomization Form 
X (*after baseline visit two 
only) 
Medical History Form 
X 
Physical Exam 
X 
X 
X 
Clinical Laboratory Form 
X 
X 
Concomitant Medications 
Form 
X 
X 
X 
Lesion/EOD Form 
X 
X 
Adverse Event Form 
X 
X 
X 
Serious Adverse Event Form 
X 
Off Study Form 
X 
Tobacco History 
X 
Alcohol History 
X 
Follow-up Tobacco Use 
Questionnaire 
X 
X 
Tobacco Cessation 
Counseling 
X 
X 
Compliance 
X 
X 
Monthly Follow-Up Phone 
Calls 
X(*weeks 2, 6, 10, 14, 18, 
and 22 ONLY) 
COX-2 by Quantitative PCR 
X 
DNA Ploidy Analysis 
X 
Ki-67 Expression by 
Immunohistochemistry 
X 
p53 Expression by 
Immunohistochemistry 
X 
Verification Form 
X 
16.1.4 Data Review and Queries for Participating Site Data 
 
Research staff at MSKCC will review data and source documentation as it is submitted. Data will be 
monitored against source documentation and discrepancies will be sent as queries to the participating 


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sites. Queries will be sent by MSKCC Research staff twice a month. 
Participating sites should respond to data queries within 14 days of receipt. 
16.1 
Quality Assurance 
 
16.1.1 Quality Assurance for Participating Sites 
 
Each site participating in the accrual of participants to this protocol will be audited by the staff of the 
MSKCC study team for protocol and regulatory compliance, data verification and source documentation. 
Audits may be accomplished in one of two ways: (1) selected participant records can be audited on-site at 
participating sites or (2) source documents for selected participants will be sent to MSKCC for audit. 
Audits will usually be determined by participant accrual numbers and rate of accrual, but can also be 
prompted by reported SAEs or request of MSKCC PI. 
 
Audits will be conducted at least once shortly after initiation of participant recruitment at a site, annually 
during the study (or more frequently if indicated), and at the end or closeout of the trial. The number of 
participants audited will be determined by available time and the complexity of the protocol. 
 
The audit will include a review of source documentation to evaluate compliance for: 
 
• 
Informed consent documents and procedures 
• 
Adherence to eligibility criteria 
• 
Protocol defined treatment 
• 
Required baseline, on study and follow-up protocol testing 
• 
IRB documents (submitted amendments, annual continuing review reports, SAEs) 
• 
Required specimen submission 
• 
Case Report Form submissions to MSKCC: timelines and accuracy 
 
A wrap-up session will be conducted at the participating site and preliminary findings will be discussed 
with the participating site PI and research team. The preliminary results will be sent to the MSKCC PI. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited participating site 
within 30 days of the audit. The report will include a summary of findings, participant by participant case 
review, specific recommendations on any performance and/or shortcomings and request for corrective 
action, when necessary. When corrective action is required, the participating site must reply within 45 
days of receipt of audit report with their corrective action plan. 
 
A copy of the audit report and corrective action plan (if applicable) submitted by the participating site 
must be sent to the MSKCC IRB/PB, CRQA and maintained in the department’s protocol regulatory 
binder. 
 
16.2 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute 


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for Data and Safety Monitoring 
of Clinical Trials” 
which 
can be found 
at:  
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. 
The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research.   The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359709/DSMPlans07.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and 
II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
In addition, our study team in collaboration with the Office of Clinical Research and the 
Office of the Physician-in-Chief has spent a considerable amount of time and effort in 
developing a tailored comprehensive data and safety management plan specific to our pilot 
multi-center international clinical chemoprevention trial. Please refer to see Appendix VI to 
view our detailed and rigorous data and safety monitoring plan. 
 
16.3 
Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the MSKCC 
Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this protocol at the 
participating sites, approval for the MSKCC IRB/PB approved protocol must be obtained from the 
participating site’s IRB. 
The following documents must be provided to MSKCC before the participating site can be initiated 
and begin enrolling participants: 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
• 
Participating Site IRB approved consent form 
• 
Participating Site IRB membership list 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• 
Curriculum vitae and medical license for each investigator and consenting professional 
• 
Documentation of Human Subject Research Certification training for investigators and key staff 
members at the Participating Site 
• 
Participating site laboratory certifications and normals 


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Upon receipt of the required documents, MSKCC will formally contact the site and grant permission 
to proceed with enrollment. 
 
16.3.1 Amendments 
Each change to the protocol document must be organized and documented by MSKCC and first 
approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC will 
immediately distribute amendments to the participating sites, for submission to their local IRBs. 
 
Participating sites must obtain approval for all non expedited amendments from their IRB within 90 
calendar days of MSKCC IRB/PB approval. If the amendment is the result of a safety issue or makes 
eligibility criteria more restrictive, sites will not be permitted to continuing enrolling new participants 
until the participating site IRB approval has been granted. 
 
The following documents must be provided to MSKCC for each amendment within the stated 
timelines: 
• 
Participating Site IRB approval 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
 
16.3.2 Additional IRB Correspondence 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of study 
activities. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who does not 
meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in their study plan.  
If a deviation from this protocol is proposed for a potential or existing participant at MSKCC or a 
participating site, approval from the MSKCC IRB/PB is required prior to the action. Participating sites 
should contact the MSKCC PI who will in turn seek approval from the MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are identified 
after they occur, the participating site should report to MSKCC as soon as possible. The MSKCC PI 
will in turn report the violation to the MSKCC IRB/PB. 
 
Participating sites should report deviations and violations to their institution’s IRBs as soon as possible 
per that site’s institutional guidelines. Approvals/acknowledgments from the participating site IRB for 
protocol deviations and violations should be submitted to MSKCC as received. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to local 
guidelines, and submit copies of that correspondence to MSKCC. 
 
 
16.3.3 Document maintenance 


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The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to enable the 
implementation of the protocol to be fully documented and the data to be subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB approval letters 
referencing protocol version date and amendment number, IRB approved protocol, appendices, 
informed consent forms, deviations, violations, and approval of continuing reviews) is maintained in 
the regulatory binder on site and sent to MSKCC. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper or 
electronic. 
 
After study closure, the participating site will maintain all source documents, study related documents 
and CRFs for 3 years. 
 
16.4 Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended and/or contract payments maybe withheld (if applicable), until the outstanding issues have 
been resolved. 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Human subjects will be provided with complete informed consent and all pertinent questions 
answered. These encounters will be documented in the medical record. Standard of care 
treatment will be provided for all subjects. The suspicion of disease progression of disease 
will trigger biopsy of lesions and withdrawal from the study. Incremental costs of research are 
not charged to subjects or their insurance carriers. Every effort is made to preserve the 
subjects’ rights during the recruitment and conduct of the study. 
 
Inclusion of Children in Research 
 
This protocol/project does not include children because the number of children is limited and 
because the majority are already accessed by a nationwide pediatric cancer research network. 
This statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion of 
Children as Participants in Research Involving Human Subjects. 
 
 
17.2 
Privacy 
 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board. 


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17.3 Serious Adverse Event (SAE) Reporting 
 
Our study team in collaboration with the Office of Clinical Research and the Office of the 
Physician-in-Chief has spent a considerable amount of time and effort in developing a 
tailored serious adverse event reporting plan specific to our  pilot  multi-center 
international clinical chemoprevention trial (Appendix VI). 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office at sae@mskcc.org containing the following 
information: 
Fields populated from the CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
The PI’s signature and the date it was signed are required on the completed report. 
17.3 Serious Adverse Event (SAE) Reporting for Participating Sites 
 
Responsibility of Participating Sites 
• 
Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or e-mail within 3 
calendar days of learning of the event. 
• 
Participating sites should notify the MSKCC PI of any grade 5 event immediately. 
• Participating sites should use the SAE Report Template (appendix IX) to report SAEs to MSKCC. 
SAE contact information for the Coordinating Center is listed below: 


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Principal Investigator:Jay O. Boyle, MD, 212-639-2906 
Research Staff: Lasha Clarke, 646-227-2224 
Responsibility of MSKCC 
• 
The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC IRB/PB as 
specified in 17.2 
• 
The MSKCC PI is responsible for informing all participating sites about unexpected SAEs within 30 
days of receiving the stamped SAE from the MSKCC IRB/PB. 
• 
Any report pertaining to a grade 5 event will be distributed to the participating sites as soon as 
possible. 
17.4 Safety Reports 
 
• 
MSKCC will distribute outside safety reports to the participating sites immediately upon receipt. 
• 
MSKCC must submit safety reports to the MSKCC IRB/PB according to institutional guidelines. 
• 
Participating sites must submit safety reports to their institution’s IRBs within 30 days of receipt 
from MSKCC or per participating site guidelines. 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details of 
the protocol and study procedures as well as the risks involved to participants prior to their inclusion in 
the study. Participants will also be informed that they are free to withdraw from the study at any time. All 
participants must sign an IRB/PB-approved consent form indicating their consent to participate. This 
consent form meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1. 
The nature and objectives, potential risks and benefits of the intended study. 
2. 
The length of study and the likely follow-up required. 
3. 
Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4. 
The name of the investigator(s) responsible for the protocol. 
5. 
The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully explain 
the aspects of patient privacy concerning research specific information. In addition to signing the IRB 
Informed Consent, all patients must agree to the Research Authorization component of the informed 
consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must receive a 
copy of the signed informed consent form. 
 
The investigators listed on the protocol cover page and their qualified designees at each participating site 
may obtain informed consent and care for the participants according to good clinical practice and protocol 
guidelines. 


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Signed copies of the informed consent should be distributed as follows: One copy will be given to the 
participant to be retained for their personal records. One copy will be maintained on file at the MSKCC. 
The third copy will be confidentially maintained by the participating institution. 
 
A note will be placed in the medical record documenting that informed consent was obtained for this 
study, and that the participant acknowledges the risk of participation. 
 
 
For AIMS and RCC subjects: three original informed consent forms will be obtained: 1) one consent form 
will be kept secure in the office of Dr. Kuriakose or Dr. Sebastian in the subject’s research and/or medical 
record, 2) one of the originals will be sent to MSKCC in batches as appropriate (see Appendix VI, Section 
D.2.b). A copy of the signed consent will be faxed to the RSA at MSKCC for registration onto the 
protocol, inclusion in the research record and entry into the CRDB at the time of consent, 3) one signed 
informed consent will be provided to the subject. 
 
For MSKCC subjects: three original informed consent/RA will be obtained: 1) one consent/RA form will 
be kept secure in the research office of the RSA, 2) another consent/RA form will be used in the 
electronic medical record and 3) one signed informed consent/RA will be provided to the subject. 
 
18.1 For Participating Sites 
 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to good 
clinical practice and protocol guidelines. 
 
Signed copies of the informed consent should be distributed as follows: One copy will be given to 
the participant to be retained for their personal records. One copy will be maintained on file at the 
MSKCC. The third copy will be confidentially maintained by the participating institution. 
 
A note will be placed in the medical record documenting that informed consent was obtained for 
this study, and that the participant acknowledges the risk of participation. 


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Engel, L. S., Taioli, E., Pfeiffer, R., Garcia-Closas, M., Marcus, P. M., Lan, Q., Boffetta, 


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P., Vineis, P., Autrup, H., Bell, D. A., Branch, R. A., Brockmoller, J., Daly, A. K., Heckbert, S. 
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20.1 
APPENDICES 
 
I. Informed Consent Form. 
 
II. Eligibility Form. 
 
III. Case Report Forms. 
 
IV. Pill Diary and Adverse Event Form. 
 
V. Shipping Instructions. 
 
VI. Data and Safety Monitoring Plan 
 
VII. Description of Amrita Institute for Medical Sciences and Research Centre (AIMS). 
 
VIII. Description of Regional Cancer Centre (RCC). 
 
IX. Zubrod Performance Status 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 62 - 
 
 
 
APPENDIX I: 
Informed Consent Form. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 63 - 
 
 
 
APPENDIX II: 
Eligibility Form. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
Amended: 2/8/13 
- 64 - 
 
 
 
APPENDIX III: 
Case Report Forms 


Amended: 2/8/13 
- 65 - 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
APPENDIX IV: 
Pill Diary and Adverse Event Form 
 
 
 


Amended: 2/8/13 
- 66 - 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
APPENDIX V: 
Shipping Instructions. 
 
 
 


Amended: 2/8/13 
- 67 - 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
APPENDIX VI: 
Data and Safety Monitoring Plan 
 
 
 


Amended: 2/8/13 
- 68 - 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
APPENDIX VII: 
Description of Amrita Institute for Medical Sciences and Research Centre (AIMS). 
 
 
 


Amended: 2/8/13 
- 69 - 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
APPENDIX VIII: 
Description of Regional Cancer Centre (RCC) 
 
 
 


Amended: 2/8/13 
- 70 - 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 04-099A(18) 
APPENDIX IX: 
Zubrod performance score.