A Randomized Study of Sulindac in Oral Premalignant Lesions

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.

Inclusion Criteria:

For this study an Oral Premalignant Lesions (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.

- The subj has a histologically suspected or confirmed index oral premalignant lesion,
12mm or greater in size that has not been bx'd in the past 6 wks. 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 or mild dysplasia, or
hyperplastic leukoplakia of high-risk sites, lateral and ventral tongue and floor
or mouth OR

- An ADVANCED premalignant lesion defined as the presence of at least one of the
following: moderate dysplasia or severe dysplasia (excluding CIS)

- The subj is > 18 yrs of age

- The subj's life expectancy is > 12 wks and Zubrod performance status is 0 or 1
(Appendix VIII).

- The subj meets the following lab eligibility criteria during a time not to exceed 4
wks prior to randomization.

- Hemoglobin level above 10g/dL for women and above 12g/dL for men.

- WBC count > 3,000 uL.

- Platelets count > 125,000 uL.

- Total bilirubin < or = 1.5xULN

- AST (SGOT) and ALT (SGPT) < or = 2.5 x ULN.

- BUN and serum creatinine < or = 1.5 x ULN.

- If the subj is female and of childbearing potential (women are considered not of
childbearing potential if they are at least 2 yrs 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 ds prior to
randomization.

- The subj's history/use of NSAIDs, aspirin, corticosteroids meets the following
criteria:

- total oral/intravenous corticosteroid use has been < 14 ds within 6 mos of the
Baseline visit, and

- total inhaled corticosteroid use has been < 30 ds within 6 mos of the Baseline
visit, and

- is willing to limit aspirin use to < or = 120 mg po per d (typical
cardioprotective dose in India) or < or = 80 mg po per d (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 inhibitors for duration of
study. Chronic use of NSAIDs is defined as a frequency of > or = 3 times/wk AND
for more than a total of 14 ds a yr.

- The subj has discontinued any other chemopreventive therapy at least 3 mos prior to
the Baseline visit and all toxicities have been fully resolved.

- If applicable, the subj has been counseled on smoking cessation.

- If the subject is male, will use adequate contraception during the study.

Exclusion Criteria:

- The subject has had chemotherapy, immunotherapy, hormonal tx (other than HRT for
menopause), or RT within 3 wks of the Baseline visit.

- The subj has not recovered from the acute toxic effects of chemotherapy,
immunotherapy, hormonal tx, or RT.

- The subj will need concurrent chemotherapy, radiotherapy, hormonal (other than HRT for
menopause), or immunotherapy during the time of study.

- The subj has a history of hypersensitivity to sulindac, COX-2 inhibitors, NSAIDs,
salicylates.

- The subj has been diagnosed with or has been treated for esophageal, gastric, pyloric
channel, or duodenal ulceration.

- The subj has a history of inv cancer within the past 1 yr (excluding non-melanoma skin
cancer and in situ cervical cancer).

- The subj 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 subj has a past history of or active inflammatory bowel disease (eg. Crohn's
disease or ulcerative colitis) or pancreatic disease.

- The subj has received any investigational medication within 30 ds of the Baseline
visit or is scheduled to receive an investigational drug during the course of the
study.

- The subj is, in the opinion of the Institutional Principal Investigator, not an
appropriate candidate for study participation.

- The subj participated in the study previously and was withdrawn.