Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryotherapy in the Hypertrophic Actinic Keratoses

The investigators plan to treat 30 subjects. Each qualifying subject will have at least 3
hypertrophic AKs, defined as more than 3mm in thickness, on each dorsal hand. Cryotherapy
will be standardized in all patients and for all treated lesions: 1-2 sprays, 5 seconds
each, with a 5 second interval. All subjects will be treated with the same cryo-spray.
Following cryotherapy, subjects will be randomized to treat either their right or left
dorsal hand with ingenol mebutate gel. The decision to treat the right vs. the left hand
will be chosen by chance, like flipping a coin. Neither the subject nor the study doctor
will choose what arm receives the ingenol mebutate gel. The study doctor will not know which
arm is treated with ingenol mebutate, so the subject should not reveal that information to
him or her at any time during the study. Subjects will treat the randomized dorsal hand with
ingenol mebutate 0.05% gel starting on the same day as the cryotherapy (Day 0). Subjects
will utilize the once daily for two days regimen. Subjects will be followed on day 4 after
their initial visit, day 8, day 15, day 29, and day 57, with a two day window period.

Inclusion Criteria:

- Adults at least 18 years old.

- Subjects must be in good general health as confirmed by the medical history.

- Subjects must be able to read, sign, and understand the informed consent

- Prior to cryosurgery, subjects have at least 3 hypertrophic actinic keratoses on each
dorsal hand.

- Subject must be willing to forego any other treatments on the dorsum of the hands,
including tanning bed use and excessive sun exposure while in the study.

- Subject is willing and able to participate in the study as an outpatient, making
frequent visits to the study center during the treatment and follow-up periods and to
comply with all study requirements including concomitant medication and other
treatment restrictions.

- If subject is a female of childbearing potential she must have a negative urine
pregnancy test result prior to study treatment initiation and must agree to use an
approved method of birth control while enrolled in the study.

Exclusion Criteria:

- Subjects with a history of melanoma anywhere on the body.

- Subjects with an unstable medical condition as deemed by the clinical investigator.

- Subjects with non-melanoma skin cancer on the dorsum of the hands.

- Subjects with any dermatologic disease in the treatment area that may be exacerbated
by the treatment proposed or that might impair the evaluation of AKs.

- Subjects who have previously been treated with ingenol mebutate: on the dorsum of the
hands in the past 6 months; or outside of the study area within the past 30 days.

- Women who are pregnant, lactating, or planning to become pregnant during the study
period.

- Subjects who have experienced a clinically important medical event within 90 days of
the visit (e.g., stroke, myocardial infarction, etc).

- Subjects who have active chemical dependency or alcoholism as assessed by the
investigator.

- Subjects who have known allergies to any excipient in the study gel.

- Subjects who are currently participating in another clinical study or have completed
another clinical study with an investigational drug or device on the study area
within 30 days prior to study treatment initiation.

- Subjects who have received any of the following within 90 days prior to study
treatment initiation:

- interferon or interferon inducers

- cytotoxic drugs

- immunomodulators or immunosuppressive therapies (inhaled/ intranasal steroids
are permitted)

- oral or parenteral corticosteroids

- topical corticosteroids if greater than 2 gm/day

- any dermatologic procedures or surgeries on the study area (including any AK
treatments)

- Subjects who have used any topical prescription medications on the study area within
30 days prior to study treatment initiation.