A seamless phase I/II dose-finding trial assessing ingenol disoxate (LEO 43204) for field treatment of actinic keratosis on the scalp

Background Actinic keratosis (AK) is a common sun-related skin condition, which can progress to squamous cell carcinoma and occur in cancerized fields. Objectives To investigate in a phase I/II trial the safety and efficacy of ingenol disoxate as topical field therapy for patients with AK on the balding scalp. Methods Part 1 was a phase I, open-label, dose-escalation trial investigating up to six doses of ingenol disoxate to determine the maximum tolerated dose (MTD). Part 2 was a phase II, randomized, double-blind, parallel group, vehicle-controlled trial. Patients were randomized 2 : 2 : 1 to receive ingenol disoxate 0.037%, 0.05% or vehicle gel once daily for two consecutive days. Percentage reduction in AK count from baseline, complete clearance (AKCLEAR 100) and partial clearance (>= 75% AK count reduction; AKCLEAR 75) were assessed at week 8. Results The MTD in part 1 was 0.075% based on a dose-dependent increase in the number and severity of adverse events. Two lower doses of ingenol disoxate gel (0.037%, 0.05%) were assessed in part 2, which showed a reduction in AK count from baseline to week 8 (0.037%, 72.7%; 0.05%, 78.5% vs. vehicle 12.6; P < 0.001), and rates of AKCLEAR 100 and AKCLEAR 75 were significantly higher in active treatment groups compared with vehicle (P = 0.007). Local skin responses peaked at day 3 and declined rapidly. Adverse events were generally mild to moderate in intensity, and were most commonly application site pain/pruritus. Conclusions Ingenol disoxate 0.037% and 0.05% gel was effective and superior to vehicle, and well tolerated as field therapy for AK on the balding scalp.