Pharmacokinetics of Ingenol Mebutate Gel in Actinic Keratosis Under Maximum Use Conditions

A Phase I, Multi-centre, Open-label, Uncontrolled, Non-randomised Study to Evaluate the Systemic Exposure and Safety of Ingenol Mebutate When Applied to Full Face, Balding Scalp or an Area of Approximately 250 cm2 on the Arm in Subjects With Actinic Keratosis

This is an open-label, uncontrolled, non-randomised multi-centre trial in which 3 parallel groups will be enrolled. The trial includes three active treatment groups.

To be eligible for inclusion in this trial, subjects must have at least 10 clinically typical, visible, and discrete AKs on the face, balding scalp or on the arm within a contiguous area of approximately 250 cm2 of sun-damaged skin.

There will be 3 treatment groups: (1) once daily application of ingenol mebutate gel 0.027% on the full face for three consecutive days, (2) the same regimen on the balding scalp, and (3) once daily application of ingenol mebutate gel 0.06% on the arm on a treatment area of approximately 250 cm2 for four consecutive days.

Inclusion Criteria:

1. Following verbal and written information about the trial, the subject must provide informed consent documented by signing the Informed Consent Form prior to any trial-related procedures.2. Subjects with at least 10 clinically typical, visible and discrete AKs on the face, on approximately 250 cm2 of balding scalp or an area of approximately 250 cm2 of sun-damaged skin on the arm except the back of the hand.

3. Subject at least 18 years of age. 4. Female subjects must be of either:

• Non-childbearing potential, i.e. post-menopausal or have a confirmed clinical history of sterility (e.g. the subject is without a uterus) or,

  • Childbearing potential, provided there is a confirmed negative urine pregnancy test prior to trial treatment, to rule out pregnancy.

    5. Female subjects of childbearing potential must be willing to use effective contraception at trial entry and until completion. Effective contraception is defined as follows:

  • Oral/implant/injectable/transdermal/oestrogenic vaginal ring contraceptives, intrauterine device, condom with spermicide, diaphragm with spermicide.

  • Abstinence or partner's vasectomy are acceptable if the female agrees to implement one of the other acceptable methods of birth control if her partner changes.

Exclusion Criteria:

1. Location of the treatment area (full face, balding scalp or arm)

   • within 5 cm of an incompletely healed wound,
   • within 10 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC).

2. Prior treatment with ingenol mebutate gel within the last three months.

3. Lesions in the treatment areas that have:

   • atypical clinical appearance (e.g., hypertrophic, hyperkeratotic or cutaneous horns) and/or,
   • recalcitrant disease (e.g., did not respond to cryotherapy on two previous occasions).

4. Any abnormal laboratory tests that are medically significant and would impact the safety of the subjects or the interpretation of the trial results, as determined by the investigator's judgment.

5. Current enrolment or participation in an investigational clinical trial within 30 days of entry into this trial.

6. In the opinion of the investigator, the subject is unlikely to comply with the Clinical Study Protocol (e.g. alcoholism, drug dependency or psychotic state).

7. Subjects with QTcF interval > 450 ms for males and 470 ms for females or other relevant pathological changes in the ECG in opinion of the investigator. These intervals apply at Screening Visit.