Trial Information

This study is to determine if a locally applied immune response modifier will eliminate high
grade dysplasia in Barrett's esophagus. Barrett's esophagus is a premalignant condition
caused by chronic reflux of gastric contents into the lower esophagus. Present practice is
to do a periodic esophagoscopy on patients with Barrett's esophagus and take biopsies in
search of dysplasia. If the pathologist reports low grade dysplasia, the patient usually
receives more intensive surveillance. If the pathologist reports high grade dysplasia, the
patient and his physician are faced with a dilema. High grade dysplasia is carcinoma in
situ and there is a strong propensity for such patients to progess to frank carcinoma of the
esophagus. Carcinoma of the esophagus is a miserable disease which is difficult to treat
and leads to death in about 95% of the cases at 5 years. The present standard for patients
with high grade dysplasia is to recommend esophagectomy. Esophagectomy is a major surgical
procedure with significant associated morbidity and mortality. Porfimer sodium(Photofrin)
photodynamic therapy is effective in eliminating high grade dysplasia in Barrett's
esophagus. It has been approved by the FDA but it is not widely utilized because of its
complexity and expense. Other modalities such as endoscopic mucosal resection and
endoscopic thermal ablation techiques are being studied. Although endoscopic techniques are
much safer than surgery, they all are uncomfortable and carry some risk. Many patients with
Barrett's esophagus are elderly and most with high grade dysplasia do not live long enough
to develop cancer. This fact has made some gastroenterolgists recommend intensive
surveillance as an alternative to the above mentioned therapeutic modalities. Intensive
surveillance in this setting means endoscopy with biopsies every 3 months with specific
therapy recommended only if frank cancer is found. This study is based upon the fact that
intensive surveillance is an acceptable way of following these patients. The only
difference is an oral agent will be added in hopes of getting rid of high grade dysplasia.
If high grade dysplasia could be eliminated by an oral medication it would be a quantum
improvement over what we have. The present belief is if high grade dysplasia is eliminated
there would be no progression to cancer.

852A is an immune response modifier being developed by 3M Pharmaceuticals. It is thought to
exert its therapeutic effect by simulating alpha interferon. 852A is similar to the immune
response modifier imiquimod(Aldara). Imiquimod is presently approved by the precancerous
dermatological condition, actinic keratosis. It is very effective. Treatment is simply
applying 5% imiquimod cream twice weekly to the skin lesion for 16 weeks. It seems
reasonable that if an immune response modifier will eliminate precancerous lesions of the
skin by local application, the same should be true for precancerous lesions of the
esophagus. In this study 852A will be swallowed to see whether it can eliminate high grade
dysplasia from the esophagus.

Entrance into the present study would be predicated on the confirmation of high grade
dysplasia in Barrett's esophagus. If the prospective subject meets all of the inclusion and
exclusion criteria set out in the protocol, endoscopic ultrasound of the esophagus would be
done. If endoscopic ultrasound shows no invasion into the submucosa the patient would be
asked to sign an informed consent. Once entered into the sudy the subject would be given
the study drug twice weekly, 3-4 days apart, for 8 weeks. 852A will be supplied in sterile
vials by 3M Pharmaceuticals. Five mg of 852A will be mixed with sterile 5% dextrose in
water to give a final volume of 30 ml. The patient will promply swallow the study drug
after it is mixed. The subject will then assume a recumbent position for 30 minutes in
hopes that the medication will stay in contact with the mucosa of the esophagus long enough
to get an effect. All doses of the study medication will be given in the principal
investigator's clinic. After the first dose is given that patient will stay in the clinic
under observation for 4 hours. Observation includes taking the temperature, pulse, and
blood pressure every hour. If there are no adverse effects after the first dose, the
observation period after subsequent doses will reduced to one hour. Laboratory tests will
be repeated 1,2,4 and 8 weeks after the first dose is given. As set out in the study
protocol, if the patient has any significant adverse event or laboratory deviation, the
subject would be dropped from the study. Throughout the study the subjects will be treated
with a double dose of a proton pump inhibitor to control gastric acid reflux.

After 8 weeks of therapy the study medication will be stopped. Four weeks thereafter and 12
weeks from the beginning, repeat endosocpy with biopsies will be done. If biopsies show no
residual high grade dysplasia, the patient will be continued in an intensive surveillance
program. Intensive surveillance means endoscopy with biopsies every 3 months for 1 year,
then every 6 months for 1 year then yearly for 3 more years. If high grade dysplsia
persists after 8 weeks of treatment or cancer is found, the patient would be referred for
conventional therapy. Likewise, if high grade dysplsia recurs or cancer is found during the
intensive surveillance program, the subject will be referred for conventional therapy.