title: A seamless phase I/II dose-finding trial assessing ingenol disoxate (LEO 43204) for field treatment of actinic keratosis on the scalp.
abstract: BACKGROUND
  Actinic keratosis (AK) is a common sun-related skin condition, which can progress to squamous cell carcinoma and occur in cancerized fields.
  
  
  OBJECTIVE
  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.
authors.affiliation: Gwinnett Clinical Research Center, Inc., Snellville, GA, U.S.A.
authors.forename: J
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Collegium Medicum Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Altman Dermatology Associates, Arlington Heights, IL, U.S.A.
authors.forename: M
authors.initials: M
authors.lastname: Bukhalo
authors.affiliation: LEO Pharma A/S, Ballerup, Denmark.
authors.forename: M L
authors.initials: ML
authors.lastname: Østerdal
authors.affiliation: LEO Pharma A/S, Ballerup, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Bang
authors.affiliation: Laser & Skin Surgery Center Indiana, Carmel, IN, U.S.A.
authors.forename: C W
authors.initials: CW
authors.lastname: Hanke
mesh_terms: D000279:Administration, Cutaneous; D000368:Aged; D000505:Alopecia / Q000150:complications; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004224:Diterpenes / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005782:Gels; D006801:Humans; D055623:Keratosis, Actinic / Q000150:complications / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012536:Scalp Dermatoses / Q000150:complications / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003879:Dermatologic Agents; D004224:Diterpenes; D005782:Gels; C000612882:LEO 43204