Pilot Study of Oral 852A for Elimination of High-Grade Dysplasia in Barrett's Esophagus

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.