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

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 for12 weeks (n=30). Based upon toxicology studies and
clinical studies in healthy volunteers and in patients with type I gastric carcinoids, the
starting dose will be 100 mg YF476 (4 x 25 mg) by mouth once daily. When 6 patients have
completed 12 weeks treatment with that dose, it may be increased to 150 or 200 mg once
daily, based on the emerging safety data. Before the dose of YF476 is increased, the
Institutional Review Board (IRB) will review the summarised safety and efficacy data from
the first 6 patients, the proposed dose schedule and the planned follow-up safety
assessments. The dose won t be increased without approval from the IRB. Patients will be
followed for endoscopic, histological, quantitative PCR, and biochemical changes during
treatment and at follow-up. 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.

- INCLUSION CRITERIA:

1. Men; post-menopausal women; pre-menopausal women who have been sterilised by
tubal ligation, hysterectomy or bilateral oophorectomy; or premenopausal women
using one of the allowed methods of contraception: condom and spermicide or
intra-uterine device.

2. Patients will have confirmed ZES (elevated gastrin, acid hypersecretion,
abnormal secretin test), treated with a PPI, and endoscopically visible gastric
carcinoids; and/or ECL cell hyperplasia/dysplasia.

3. Patients with serum gastrin > 250 pg/mL.

4. Hepatic function: AST and ALT less than or equal to 2.0 times ULN; total
bilirubin less than or equal to 1.0 times ULN.

5. Renal function: serum creatinine < 1.0 times ULN.

6. Haematologic function: Hb greater than or equal to 10.0 g/dL; WBC greater than
or equal to 3.5 times 10(9)/L; ANC greater than or equal to 1.5 times 10(9)/L;
platelets greater than or equal to 100 times 10(9)/L.

7. Coagulation parameters: INR or PT less than or equal to 1.0 times ULN; PTT less
than or equal to 1.0 times ULN.

8. Ability to communicate satisfactorily with the investigator and to participate
in, and comply with the requirements of, the entire trial.

9. Willingness to give fully-informed, written consent.

EXCLUSION CRITERIA:

1. Patients under 18 years.

2. Women who are pregnant, lactating or using a steroid contraceptive.

3. Prior gastric resection or bypass.

4. Planned gastrinoma resection during the study period.

5. Patients on somatostatin analogues, except for those on therapy for greater than or
equal to 6 months with stable or worsening carcinoids

6. Inability to tolerate endoscopy, or refusal of endoscopy.

7. Physical findings, ECG (especially prolonged QTc interval > 450 msec), or laboratory
values at the pre-trial screening assessment that could interfere with the objectives
of the trial or the safety of the subject.

8. Certain medicines and herbal remedies taken during the 7 days before Visit 2.

9. Participation in a trial of an IMP within the previous 28 days.

10. Presence of drug or alcohol abuse.

11. History or baseline findings of:

- Type I diabetes mellitus;

- Pancreatitis (baseline amylase and/or lipase greater than or equal to 2.0 times
the ULN);

- Hepatitis B, hepatitis C or HIV;

- malabsorption syndrome or inability to swallow or retain oral medicine;

- Major surgery less than or equal to 28 days prior to enrollment;

- ECOG performance status greater than or equal to 2; or

- Another cancer within 3 years except for basal carcinoma of the skin or cervical
carcinoma in-situ.

- Also, any clinically significant and uncontrolled major morbidity including but
not limited to: serious cardiac disease (unstable angina, s/p myocardial
infarction less than or equal to 1 month); respiratory disease (advanced COPD or
pulmonary fibrosis); uncontrolled hypertension; or active systemic infection.

12. Medically documented ongoing psychiatric illness, unless determined to be an
acceptable candidate by an NIH psychiatric consultant.

13. Inability to give informed consent.