A Pilot Trial of YF476, A Gastrin Antagonist, in Patients With Type II Gastric Carcinoids Associated With Zollinger-Ellison Syndrome
18 Years
N/A
Both
Carcinoid
Trial Information
A Pilot Trial of YF476, A Gastrin Antagonist, 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 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.
Inclusion Criteria
- 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. The first 10 patients will have confirmed ZES (elevated gastrin, acid
hypersecretion, abnormal secretin test), treated with a PPI, and endoscopically
visible gastric carcinoids; subsequent patients will have confirmed ZES (treated
with a PPI) and 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.
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
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.
Outcome Time Frame:
4.5 years
Safety Issue:
No
Principal Investigator
Stephen A Wank, M.D.
Investigator Role:
Principal Investigator
Investigator Affiliation:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Authority:
United States: Federal Government
Study ID:
110114
NCT ID:
NCT01322542
Start Date:
March 2011
Completion Date:
December 2015
Related Keywords:
- Carcinoid
- Gastrin Antagonist
- Gastrin
- Zollinger-Ellison Syndrome
- Gastric Acid
- Gastric Carcinoid Tumors
- ZES
- Gastric Tumors
- Carcinoid Tumor
- Zollinger-Ellison Syndrome
- Gastrinoma
Name | Location |
|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |
