YF476 in Patients With Type II Gastric Carcinoids Associated With Zollinger-Ellison Syndrome

• To assess if YF476 can cause regression of gastric carcinoids in patients with ZES, defined as: a 25% reduction in the size or number of endoscopically evident type II gastric carcinoids; or a reduction of 25% in the gastric ECL cell density. [ Time Frame: 4.5 years ] [ Designated as safety issue: No ]
  

• To assess if YF476: improves the histological grade of gastric carcinoids and/or ECL cell hyperplasia and affects the blood levels of biomarkers (e.g., gastrin, cahromogranin A [CgA]) [ Time Frame: 4.5 years ] [ Designated as safety issue: No ]
  

Drug: YF476
N/A

Carcinoids are tumors derived from a special type of cell called a neuroendocrine cell. Most arise within the gastrointestinal tract. Gastric (stomach) carcinoid tumors arise from the type of neuroendocrine cells called enterochromaffin-like (ECL) cells. There are three types of gastric carcinoids. Types I (80%) and II (5%) gastric carcinoids develop in response to the high levels of the hormone gastrin associated with chronic atrophic gastritis/pernicious anemia and Zollinger-Ellison syndrome (ZES), respectively. High levels of gastrin, in addition to stimulating acid secretion, can cause abnormal growth of ECL cells, which can lead to the development of gastric carcinoid tumors. Patients with ZES and the rare genetic condition multiple endocrine neoplasia type 1 (MEN-1) have a 20-30 fold higher chance of developing a gastric carcinoid than patients with ZES without MEN-1. Up to 20% of patients with ZES and MEN-1 develop type II gastric carcinoids, and in up to 30% of them, carcinoids will eventually

spread to other parts of the body (typically slowly). Gastric surgery is the usual treatment for carcinoids with features suggesting high risk of spreading. YF476 (netazepide), a potent, orally active, highly selective, blocker of gastrin receptors, might prevent the need for surgery as well as afford better control of the increased gastric acid secretion seen in patients with ZES. Non-clinical studies support the administration of YF476 to humans for up to 13 weeks. To date, YF476 has been given to 184 healthy subjects, and has been well tolerated. The pharmacological profile of YF476 in healthy subjects matches that of laboratory animals. The FDA and the EMA have designated YF476 an Orphan Drug for treatment of gastric carcinoids in the USA and the European Union, respectively.

The purpose of this protocol is to find out whether treatment with YF476 is safe and effective at achieving regression of type II gastric carcinoid tumors, or the abnormal growth of gastric ECL cells, in patients with ZES. We propose a single-center, phase II, open-label, pilot study of YF476 for up to 12 weeks (n=30). Based upon toxicology studies and initial studies in healthy volunteers, the first 6 patients will be started on 50 mg YF476 (2 x 25 mg) by mouth once daily. The dose may be increased to 75 or 100 mg once daily or reduced to 37.5 mg once daily according to an FDA algorithm based on the emerging safety profile of YF476. Patients will be followed for endoscopic, histological, quantitative PCR, and biochemical changes during treatment at weeks 6 and 12. The primary objective is to assess endoscopic and histological regression, defined as a 25% reduction in the size or number of endoscopically visible type II gastric carcinoids, or a reduction of 25% in the gastric ECL cell density. Secondary objectives are to assess if YF476 maintains control of gastric acid secretion and if it improves: the histological grade of gastric carcinoid tumors; biochemical markers; and ECL cell-specific products, assessed by quantitative PCR. Safety of YF476 will be monitored by: vital signs; ECGs; blood and urine tests; adverse experiences; and peak and trough plasma YF476 concentrations, to assess whether YF476 accumulates with dosing. Upper endoscopy with biopsy will be repeated 12 weeks after stopping YF476 in only those patients who respond to therapy.