Trial Information

Combination Therapy With Imiquimod Cream 5% and Tazarotene Cream 0.1% for the Treatment of Lentigo Maligna

Objectives

The objectives of the study are:

1. reduce the surgical morbidity of staged excisions which often require multiple stages
of surgery in order to verify negative histologic margins

2. investigate the addition of a topical retinoid, to our standard-of-care (topical
imiquimod and staged-excision) and evaluate if there is improvement in efficacy

3. to see if treatment of surrounding normal appearing skin with this combination of
topical agents reduces recurrence rates compared to staged-excision. Our hypothesis is
that the combination of topical agents will better treat the subclinical melanocytic
atypia which can give rise to recurrences.

Primary endpoint:

The primary goal is a comparison of the number of stages required for negative histologic
margins in the imiquimod plus tazarotene group compared to the imiquimod group. Tumors
requiring 5 or more stages in will be combined into one category for data analysis. The
Wilcoxon-Mann-Whitney test will be used for statistical comparison.

Secondary endpoints:

1. Comparison of the surgical defect size (mm2) between the study groups. The difference
in area between the entire surgical defect and the original tumor (as recorded on
transparent plastic) will be calculated for each patient and used as an endpoint.

2. Comparison of skin inflammation between the study groups. Skin inflammation will be
recorded as an ordered categorical variable with four categories (0-3) as described in
Section 5.

3. The type of surgical repair required (i.e. primary repair, skin flap, skin graft).

4. Immunostaining to evaluate inflammatory infiltrate. Immunostaining will be analyzed as
an ordered categorical variable.

5. Recurrence of the tumor at 3 months, 6 months, 12 months, and yearly for the next four
years.

6. The proportion of patients with skin ulceration.

7. The relationship between ulceration, skin inflammation and clearance of LM.

Study Procedures A total of eighty patients, over a twelve-month period, will be recruited
from one center for this open label study. Forty patients will be randomly assigned to one
of two treatment groups as mentioned in the Study Design section. The study will consist of
4 phases: (1) Enrollment and screening period to evaluate skin cancer, measure and trace
its perimeter; (2) 12 week treatment with topical application of study drug(s); (3) Surgical
excision of treatment site to ensure eradication of the tumor; (4) Follow-up period to rule
out recurrences.

All patients must have a biopsy-proven diagnosis of lentigo maligna confirmed by at least
two dermatopathologists from the Department of Dermatology at the University of Utah School
of Medicine. At the initial examination the clinical borders of the lesion will be defined
using a Wood's lamp (360nm) and the perimeter will be outlined with a gentian violet marker
and photographed for the medical record. (Wood's lamp examination helps to identify
pigmentary alterations of the skin when are sometimes difficult to appreciate under normal
lighting conditions.) At the time of enrollment, to rule out an invasive melanoma, all
potential study participants will undergo a shave biopsy of their lesion using local
anesthesia. Enrollment will not occur until the biopsy has been examined and confirmed to be
a lentigo maligna (melanoma in-situ). If an invasive melanoma is found, the patient will be
excluded from the study and additional evaluation/therapies implemented. If the patient is
enrolled in the study, a piece of their biopsy specimen will be used to perform
immunohistochemistry to evaluate the inflammatory infiltrate. A similar series of
histochemical staining will be performed at the conclusion of the study using a piece of the
excised skin.

Topical imiquimod group:

Patients randomized to this group will have the perimeter of the LM site, as defined by a
Wood's lamp examination, drawn on the skin with a gentian violet pen and photographed with a
Polaroid camera . One photograph will go to the medical record and the second given to the
patient to help identify the proposed treatment area. The gentian violet perimeter will then
be copied on transparent plastic to facilitate tumor localization since the tumor is
predicted to disappear clinically during treatment. The patients will then treat the LM site
two centimeters beyond the perimeter margin with topical imiquimod 5% cream Monday thru
Friday of each week for a total of twelve weeks. After three months of topical treatment, a
one-month wash out period will be observed to allow for resolution of inflammation that can
obscure the pathologist's ability to evaluate the excised tumor/treatment site. A staged
excision will then be performed with two millimeter margins around the original tumor
perimeter as previously recorded on transparent plastic which will be placed on the
patient's skin to outline the perimeter accurately. Once negative margins are confirmed
histologically, post-operative defect size will be measured in mm2 and then a plastic
surgical repair will be performed to optimize cosmesis.

Topical imiquimod and topical tazarotene 0.1% cream group:

Patients randomized to this group will undergo an identical treatment protocol as the
topical imiquimod group with the addition of topical tazarotene 0.1% cream on Saturday and
Sunday of each week.