Topical Chemoprevention of Skin Cancer Biomarkers

Men and women (≥ 18 yo)who have been seen as patients in the Dermatology Clinic at the
University of Alabama at Birmingham with a history of basal cell or squamous cell carcinoma
of the skin and at least 8 actinic keratoses on the upper extremities are potentially
eligible for study participation.

We propose to examine one topical medication which is already FDA approved,with a placebo
comparator. The purpose of the study is to see if diclofenac applied daily will affect levels
of specific biomarkers in the skin that are associated with risk of developing skin cancer.
We hope to see these levels decrease with once daily use of this medication. Results from
this study will help guide us in a second study where we will look at longer term use of
these medications and how they are associated with changes in skin biomarkers that are
related to skin cancer. The second longer study will use the dose (once or twice daily
topical application of diclofenac and DMFO) that resulted in a decrease in biomarkers, as
discovered in this currently proposed study.

Inclusion Criteria:

o Ability to understand and willingness to sign a written informed consent document

- ECOG performance status 0-1

- Willing and able to participate for the full duration of the study

- Greater than 4 weeks from:

Prior major surgery for any indication Prior chemotherapy, hormonal therapy or radiation
therapy for cancer o Willing to abstain from: The application of topical medications
including prescription and over the counter preparations (e.g. Topical preparations
containing corticosteroids or vitamin A derivatives) to areas of actinic damage for the
duration of the study. Use of moisturizers/emollients and sunscreens on these areas is
allowed.

Chronic (defined as > 3 times/week for more than 2 consecutive weeks/year) NSAID and COX-2
inhibitor use (other than cardioprotective doses of aspirin < 100 mg po QD) for the
duration of the study. For routine analgesia, subjects may take acetaminophen as necessary.

- Normal organ and marrow function defined as laboratory values falling within the
specified ranges for the following tests (performed within 14 days of registration)
Hematologic • WBC > 3,000/ul • Hemoglobin > lower limit of normal • Platelet count >
100,000/ul Hepatic

• Total bilirubin < 1.5 X ULN

• AST (SGOT) < 1.5 X ULN

- ALT (SPGT) < 1.5 X ULN Renal

- Serum creatinine < 1.5 X ULN

- BUN < 1.5 X ULN

- Females of childbearing potential must:

Have been using adequate contraception (abstinence, IUD, birth control pills or spermicidal
gel with diaphragm or condom) since their last menses Have a documented negative serum
pregnancy test within 14 days prior to the first dose of study medication Females are not
considered to be of childbearing potential if they are at least 1 year post-menopausal or
have had a tubal ligation, bilateral oophorectomy or hysterectomy.

o The effects of topical DFMO + topical diclofenac on the developing fetus are unknown.
Therefore all females of childbearing potential must agree to use adequate contraception
(abstinence, IUD, birth control pills, or spermicidal gel with diaphragm or condom) for the
duration of study participation.

Exclusion Criteria:

o Within 6 months prior to randomization: Use of oral or intravenous corticosteroids for
more than 2 consecutive weeks Use of inhaled corticosteroids for more than 4 consecutive
weeks

o Any of the following in the 4 weeks (or as indicated) prior to randomization: Major
surgery for any indication Cytotoxic chemotherapy for any indication (including
methotrexate for arthritis) Anti-cancer treatment of any type other than for a stage 0-2
non-melanoma skin cancer Hormonal therapy for cancer prevention (including tamoxifen) Note:
treatment with finasteride/dutasteride for BPH does not render a participant ineligible.

Radiation therapy Topical medications for the treatment of actinic keratosis or skin cancer
(retin A, 5-FU, imiquimod) in the 6 months prior to randomization.

Laser resurfacing, dermabrasion, cryotherapy, chemical peel and electrodissection ±
curettage in the 6 months prior to randomization.

Nasally inhaled corticosteroids (except mometasone - Nasonex) Aspirin (>100 mg/day) - Note:
cardioprotective doses (< 100mg/day) are acceptable.

NSAIDs (other than aspirin < 100mg/day) or COX-2 inhibitors > 3 times/week for more than a
two week period Topical steroids

o Any personal history of: Invasive cancer diagnosed or treated within the past 5 years.
Participants who have been in remission for 5 years or more and have not required treatment
in the past 5 years may be eligible if the principal investigator believes there is little
to no risk of recurrence.

Solid organ or bone marrow transplant Keloid formation Photosensitivity disorder
Hypersensitivity or adverse reactions to nonsteroidal anti-inflammatory agents or to DFMO
Any disease that predisposes to NMSC An immunodeficiency disorder or the use of an
immunosuppressive drug Any skin disease that would interfere with interpretation of results

- Any family history of Ornithine diaminotransferase deficiency in a first degree
relative

- Concurrent use of the following medications or treatments Anticoagulants including
warfarin and heparin Other NSAIDs (other than aspirin <100 mg/day) on a daily basis
Topical chemotherapy, cryotherapy, radiotherapy or any other skin lesion treatment to
areas of skin being followed in this study Systemic therapy with psoralens,
immunotherapy, retinoids, or radiation therapy Cytotoxic chemotherapy for any reason
(including methotrexate for arthritis) Laser resurfacing, dermabrasion or chemical
peels Topical or systemic immunosuppressive therapy.

- Females who are pregnant or lactating. Should a woman become pregnant or suspect she
is pregnant while she is participating in this study she should notify the study
physician immediately.

- Uncontrolled concurrent illness including ongoing or active infection, psychiatric
illness/social situations that would limit compliance with study requirements or other
underlying serious medical condition which, in the investigator's opinion, might
preclude study participation.