Trial of a Gastrin Receptor Antagonist in Barrett's Esophagus

The association between gastro-esophageal reflux disease (GERD) and cancer of the esophagus
is well-established. Barrett's esophagus (BE) is a condition in which the lining of the part
of the esophagus changes to look like small intestine, and this change occurs in the setting
of GERD. Patients with BE are at increased risk for developing esophageal cancer. It is
recommended that all patients with BE take medicines called proton pump inhibitors (PPIs),
which greatly reduce the acid produced by the stomach, in the hopes of reducing the risk of
esophageal cancer. However, by reducing the acid level in the stomach, levels of a hormone
called gastrin are increased. There is laboratory data to suggest that gastrin may have
effects that actually promote the development of cancer, including esophageal cancer. The
investigators previously showed that BE patients with very high gastrin levels are more
likely to have either advanced precancerous changes (also called high grade dysplasia) or
cancer of the esophagus. As such, the obvious question is raised: does gastrin promote the
development of cancer in BE? YF476 is a new drug that blocks the effects of gastrin. Trials
in healthy subjects have demonstrated that the drug is safe and well-tolerated. The
investigators therefore propose to conduct a randomized placebo-controlled trial of YF476 in
patients with Barrett's esophagus. The primary hypothesis is that treatment with YF476 will
reduce the expression of tissue markers that are associated with an increased risk of
developing esophageal cancer.

Inclusion Criteria:

- Age >= 18 years, with histologically confirmed diagnosis of Barrett's Esophagus
without dysplasia

- Minimum of 1 cm circumferential Barrett's mucosa on endoscopy or at least 2 cm maximal
contiguous extent of Barrett's mucosa

- Proton pump inhibitor use at least once daily for at least twelve months prior to
enrolment, and stable dose of PPI for the three months before enrolment

- ECOG performance status ≤ 2 and Karnofsky ≥ 60%

- Normal organ and marrow function

- Use of adequate contraception during the study

- Willingness to comply with all treatment and follow up procedures

- Ability to understand and the willingness to sign a written informed consent document

- Up to date with all age appropriate cancer screening tests, as per American Cancer
Society guidelines

Exclusion Criteria:

- Histologically confirmed BE with high grade dysplasia, invasive carcinoma of the
esophagus, low grade dysplasia

- Prior endoscopic therapy for BE

- History of esophageal or gastric surgery

- History of atrophic gastritis, pernicious anemia, or Zollinger-Ellison syndrome

- Participation in a trial of an investigational medicinal product within the previous
28 days

- Prolonged QTc interval >450 msec

- History of allergic reactions attributed to compounds of similar chemical composition
to YF476

- History of baseline findings of: diabetes mellitus requiring insulin therapy;
pancreatitis; hepatitis B, hepatitis C or HIV; malabsorption syndrome or inability to
swallow or retain oral medicine; major surgery ≤ 28 days prior to enrollment; ECOG
performance status ≥ 2; or another cancer within 3 years except for basal carcinoma of
the skin or cervical carcinoma in situ; any clinically significant and uncontrolled
major morbidity

- Certain medicines and herbal remedies taken during the 7 days before the start of
study drug

- Has evidence of cancer at the time of enrolment, or has surveillance tests planned
within 21 weeks after enrollment