Sulindac in Preventing Melanoma in Healthy Participants Who Are at Increased Risk of Melanoma

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well sulindac works in preventing melanoma in healthy participants who are at increased risk of melanoma. Sulindac may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether sulindac is more effective than a placebo in preventing melanoma in individuals with many moles and abnormal moles.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine sulindac and metabolite levels in healthy participants with atypical nevi and benign nevus at increased risk for melanoma treated with sulindac versus placebo. SECONDARY OBJECTIVES: I. To assess the effects of sulindac on apoptosis in atypical nevi of these participants. II. To assess the effects of sulindac on VEGF expression in atypical nevi of these participants. III. To assess sulindac and metabolite levels in plasma and its association with drug levels in the target tissue. OUTLINE: This is a multicenter study. Participants are randomized to 1 of 2 treatment arms. ARM I: Participants receive oral sulindac twice daily. ARM II: Participants receive oral placebo twice daily. In both arms, treatment continues for 8 weeks in the absence of unacceptable toxicity. Blood and tissue samples are collected at baseline and/or after completion of study therapy and analyzed for sulindac and metabolite levels via high performance liquid chromatography tandem mass spectrometry; the detection of apoptotic cells via TUNEL assay; and VEGF expression via immunohistochemistry assays. After completion of study therapy, participants are followed for 2 weeks.

Official Title
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Phase II Trial of Sulindac in Individuals at Increased Risk for Melanoma

Conditions
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Precancerous Condition

Intervention / Treatment
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* Drug: sulindac
* Other: placebo
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Criteria: Healthy participants at risk for developing melanoma and meeting the following criteria: must have >= 4 large (>= 5 mm and < 15 mm) atypical nevi and have 1 benign nevus amenable to biopsies No histologically confirmed melanoma on the baseline biopsy No more than 1 prior cutaneous melanoma One prior stage I, IIA, or IIB melanoma allowed provided patients have been off treatment > 3 months Modified dermoscopy score < 4.8 Karnofsky performance status 80-100% ANC >= 1,500/mm^3 No family history of melanoma involving >= 2 first degree relatives Platelets count >= 100,000/mm^3 Total bilirubin =< 2.0 mg/dL AST/ALT =< 2.0 times upper limit of normal Creatinine =< 1.5 mg/dL Not pregnant or nursing Fertile patients must use effective contraception More than 6 months since prior and no concurrent tanning bed use or other methods to promote sun-tanning Willing to minimize sunlight exposure by applying sunscreen/sunblock or wearing clothing to shield skin during outdoor activity during study participation Willing or able to limit alcohol consumption to less than 3 servings a week during the study period No frequent, chronic or moderate/severe gastrointestinal (GI) complaints Upper GI problems requiring prescription or nonprescription medical remedies for symptoms of heartburn, dyspepsia, nausea, or abdominal pain > once a week on average History of peptic ulcer, occult or gross intestinal bleeding No prior allergic reaction to aspirin (unless subsequent dosing with other NSAIDs has been well tolerated) No history of allergic reaction to lidocaine or xylocaine No history of allergic reaction (e.g., urticaria, asthma, or rhinitis) or gastric intolerance attributed to compounds of similar chemical or biological composition to sulindac No invasive cancer or cancer treatment within the past 5 years, except nonmelanoma skin cancer No immunosuppression by medication or disease, including any of the following: AIDS, oral prednisone, immunosuppressant/immunomodulator (i.e., cyclosporine, chemotherapeutic agent, or biologic therapy) No uncontrolled intercurrent illness No ongoing or active infection No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No psychiatric illness/social situations that would limit compliance with study requirements At least 30 days since prior participation and no concurrent enrollment or planning to enroll in another clinical trial No NSAIDs for more than 5 days per month within the past 3 months and no concurrent non-study NSAIDs, except low dose aspirin (81 mg/day) Willing or able to refrain from herbal medicines, above-standard vitamins, or minerals during study Standard daily multivitamin/mineral supplement (i.e., therapeutic doses of calcium and vitamin D for osteoporosis) allowed No concurrent lithium, phenytoin, or sulfonamides WBC >= 3,000/mm^3 No history of bleeding or clotting disorder At least 3 months since prior and no concurrent coumadin or other systemic anticoagulant other than aspirin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Participants receive oral sulindac twice daily for 8 weeks | Drug: sulindac<br>* Given orally<br>* Other names: SULIN;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm II<br>Participants receive oral placebo twice daily for 8 weeks | Other: placebo<br>* Inactive agent<br>* Other names: PLCB;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sulindac Concentration in the Nevi (Moles) |  | 8 weeks | 
| Sulindac Sulfone, an Active Metabolite of Sulindac, Concentration in the Nevi |  | 8 weeks | 
| Sulindac Sulfide, an Active Metabolite of Sulindac, Concentration in the Nevi |  | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sulindac Effects on Apoptosis in Atypical Nevi | Change in the expression of a marker of apoptosis, cleaved caspase 3, in melanocytic junctional component | Baseline and 8 weeks | 
| Sulindac Effects on Vascular Endothelial Growth Factor (VEGF) Expression in Atypical Nevi | Change in VEGF expression in melanocytic junctional component | Baseline and 8 weeks | 
| Association Between Plasma and Target Tissue Sulindac Levels |  | 8 weeks | 
| Association Between Plasma and Target Tissue Sulindac Sulfone Levels |  | 8 weeks | 
| Association Between Plasma and Target Tissue Sulindac Sulfide Levels |  | 8 weeks |