Trial Information

1% Topical Pimecrolimus Cream for the Prevention of Rash Associated With the Use of the EGFR Antagonist, Cetuximab

Adult patients who are being treated with cetuximab for a malignancy will be offered the
chance to take part in the study. Patients must provide written informed consent in order
to participate in the study (including consent to clinical photographs).

The area of skin to be treated with investigational cream will be the face. Baseline
photographs will be taken of the selected area of bilateral face.

Patients will be requested to apply a thin layer of the investigational cream twice daily to
one half of face at the same time they are started on cetuximab. Patients will be provided
with a placebo cream to apply to the other side of their face. Patients will be provided
the sufficient investigational cream free of charge for the duration of study. The study
coordinator will instruct the patient regarding which side of the face to apply the
investigational cream. This will be randomly assigned by the study coordinator based on a
randomization list generated by the biostatistics core and will only be known to the study
coordinator. The dermatologist and study investigators will remain blinded to the side to
which the investigational cream was applied. In this manner, patients will serve as their
own controls. Patients are free to use oral tetracyclines if recommended by their primary
oncologists. Patients on the trial, however, cannot use another rash treatment with the
exception of moisturizing agents.

Patients participating in the study will be instructed to apply a moisturizing cream,
lotion, or ointment of their choice to the face three times a day. Moisturizers should be
applied to the skin after, not before, the investigational cream application. Patients
should not wet the treated area of skin for one hour after applying investigational cream,
otherwise it could be washed off. The investigational cream should not be applied at or near
the eyes. Patients on study will be instructed to minimize sun exposure and to avoid
exposure to artificial sunlight. Patients should apply sunscreen to when exposed to
sunlight, after the investigational cream has been completely absorbed into the skin.

Patients will be given a copy of the Dermatology Life Quality Index (DLQI) questionnaire and
asked to complete it on all study visits. Patients will be given help to complete the
questionnaire if needed. The questionnaire and its interpretation are listed in the
appendix.

Patients will be assessed at least every two weeks in person. These visits may coincide with
appointments with their primary oncologist for the treatment of their cancer. Patients will
be able to contact the study coordinator during the duration of the study. Patients will
also be requested to contact the study coordinator or investigators if the rash appears to
worsen.

The rash will be assessed by their treating oncologist during each study visit. Their
treating oncologist will remain blinded to the side which the pimecrolimus cream was
applied. Clinical photographs of the rash will be taken.

When the rash appears predominantly on the side to which pimecrolimus was applied and the
rash appears to worsen in the first 24 hrs of application of pimecrolimus then the patient
will be considered allergic to pimecrolimus, and the treatment will be stopped.

The rash will be compared at both sides of the face documented using the National Cancer
Institute Common Terminology Criteria (NCI CTC) for acneiform rash. A papule and pustule
count will also be determined by the study dermatologist and documented from the clinical
photographs. Toxicity of topical pimecrolimus therapy will also be assessed as described in
the appendix. Toxicity assessment will be described using NCI CTC Version 4. Toxicities
observed will be defined as related (definitely, probably, possibly) or unrelated to topical
pimecrolimus treatment.

The total duration of the study will be for four weeks. After two weeks on topical
pimecrolimus patients will be requested to come to a study visit. This will be coordinated
with their usual oncologist visit if possible.

After the rash assessment at this visit, the treating oncologist and the patient will be
unblinded. If the intensity of the rash in the treated area is no worse than in the
corresponding untreated area on the opposite side using the NCI CTC version 4 scale for
acneiform rash, no severe toxicities occurred in the patient, and the patient finds the
pimecrolimus therapy tolerable, the patient will continue on study. At this study visit,
patients will also be given a copy of the DLQI and asked to complete it. Patients will be
given help to complete the questionnaire by the study coordinator if needed. The
questionnaire and its interpretation are listed in the appendix. Clinical photographs will
be taken.

Patients who experience a worsening of rash intensity by NCI CTC Version 4.0 at a treated
area, or who suffer a severe toxicity (grade 3 or 4) related to topical pimecrolimus, or who
find the topical pimecrolimus intolerable will discontinue use of pimecrolimus to that area
immediately and will come off study.

Patients who continue on study after the two week visit may apply a thin layer of 1% topical
pimecrolimus twice daily to both sides of face.

Patients who continue pimecrolimus therapy, beyond the initial rash assessment, will be
re-assessed after two weeks in the same manner as at the initial rash assessment. Patients
will remain on study for a maximum of 4 weeks since starting pimecrolimus therapy. At the 4
week study visit, patients will also be given a copy of the DLQI and asked to complete it.
Patients will be given help to complete the questionnaire by the study coordinator if
needed. The questionnaire and its interpretation is listed in the appendix

Patients who are considered to have benefited from pimecrolimus therapy at the 4 week visit
may choose to use commercially available pimecrolimus off protocol but will be advised that
the safety of topical pimecrolimus has not been established beyond one year of use, and that
insurance might not cover for treatment.

RATIONALE FOR STUDY DESIGN

There is no highly-effective treatment for epidermal growth factor receptor (EGFR)-inhibitor
induced rash. In this study patients will be offered 1% pimecrolimus cream, in addition to
other standard non-topical therapy such as oral tetracycline antibiotics and moisturizing
agents. Patients will apply 1% pimecrolimus cream to one side of the face at the time of
starting cetuximab. The opposite untreated side will serve as the control side. In this
controlled manner, if a decrease in papule and pustule count and/or rash severity per NCI
CTC version 4.0 with the use of topical pimecrolimus, without severe or intolerable toxicity
is demonstrated in this pilot study, further large scale studies of this therapy may be
warranted.