EA6232: A phase II double-blind trial of sulforaphane for therapeutic prevention of melanoma in patients with multiple atypical nevi and a prior history of melanoma.

Abstract

TPS9611 Background: A significant risk factor for melanoma is presence of atypical/dysplastic nevi (A/DN), and evidence suggests a 10-fold increased risk of new primary melanoma with A/DN. 1 Patients with prior melanoma and multiple A/DN are thus reasonable targets for therapeutic prevention due to high risk of additional melanoma. Currently, no preventative systemic agent for melanoma is approved. Sulforaphane, an isothiocyanate of cruciferous vegetables, demonstrates therapeutic prevention potential in multiple clinical trials. 2 3 Topical sulforaphane mitigates effects of UV radiation, a primary driver of melanoma development, in mouse and human skin. 4 The proposed mechanism involves alterations of transcription factor Nrf2, an antioxidant modulator, and IL-6/STAT-3 pathways in A/DN and melanoma. 5 6 7 Our team conducted a phase I trial of oral sulforaphane for 28 days in 17 patients with prior melanoma and ≥ 2 A/DN. 8 Statistically significant decreases in several serum pro-inflammatory cytokines were reported with no dose-limiting toxicities. This phase II trial aims to elucidate effects of daily sulforaphane on A/DN lesions and compare pigmentation change to placebo over one year. We hypothesize sulforaphane will demonstrate a greater decrease in total area of pigmented nevocellular nevi (both A/DN and banal nevi) vs. placebo as documented by serial digital photography. Methods: This phase II trial (NCT07040280) will assess impact of daily sulforaphane for 12 months vs. placebo on total area, quantity, and features of A/DN. Patients with ≥ 3 clinical A/DN (≥ 5 mm diameter with macular component, and ≥2 features of ill-defined borders, color variegation, uneven contour, or erythema) and a history of early stage-melanoma are eligible. Enrolled patients will undergo a baseline clinical skin exam and scheduled follow-up exams every 3 months. Photography of index A/DN and a standardized area of the posterior trunk, excisional biopsy of an A/DN, and peripheral blood sampling will be performed at baseline, 3 months, and 12 months. The primary endpoint is effect of sulforaphane vs. placebo on change in total area of pigmented nevocellular nevi on the posterior trunk at 12 months, calculated by Derma-AI image analysis software. 9 Secondary endpoints are number of posterior truncal nevi with moderate to significant changes in area, changes in A/DN features/area, and assessment of the safety/tolerability of sulforaphane. Exploratory endpoints include effects on circulating cytokine and chemokine levels assessed by multiplex technology, impact on A/DN immune cell infiltration by histopathology and immunochemistry, and evaluation of prespecified A/DN features at each timepoint. Outcome measures will be compared between arms over serial timepoints by Wilcoxon rank sum test. The study is open for enrollment with accrual goal of 120 patients.