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

Carcinoid Clinical Trial

Official title:

A Pilot Trial of YF476, A Gastrin Antagonist, in Patients With Type II Gastric Carcinoids Associated With Zollinger-Ellison Syndrome

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01322542
• Other study ID #: 110114
• Secondary ID: 11-DK-0114
• Status: Recruiting
• Phase: Phase 2
• First received: March 23, 2011
• Last updated: January 16, 2016
• Start date: March 2011
• Est. completion date: December 2017

Study information

• Verified date: January 2016
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Stephen A Wank, M.D.
• Phone: (301) 496-4202
• Email: stevew[@]bdg10.niddk.nih.gov
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Background:

• Zollinger-Ellison syndrome (ZES) is a rare condition in which one or more tumors (gastrinomas), usually in the small intestine or pancreas, produce high levels of the hormone gastrin. High levels of gastrin can cause several problems: (1) excessive growth of stomach cells; (2) excessive production of stomach acid, which can cause stomach or intestinal ulcers; and (3) growth of an unusual type of stomach tumor called a type II gastric (i.e., stomach) carcinoid. Patients with ZES suffer mainly from the effects of severe ulcer disease, but gastrinomas and gastric carcinoids both have the potential to spread throughout the body. Gastric surgery is the usual treatment for problematic carcinoids. YF476, an experimental medication, may block the effects of gastrin, which may reduce the need for surgery as well as provide better control of stomach acid in patients with ZES. Researchers are interested in studying YF476 in individuals with ZES who also have or may develop type II gastric carcinoids.

Objectives:

• To evaluate the safety and effectiveness of YF476 in reducing the size, number, or significance of type II gastric carcinoids or their precancerous cells.

• To study the effects of YF476 on stomach acid production.

Eligibility:

• Individuals at least 18 years of age who have been diagnosed with Zollinger-Ellison syndrome and type II gastric carcinoids or their precancerous cells.

Design:

• This study will involve a screening visit and five study visits.

• Participants will be screened with a physical examination and medical history, as well as blood tests.

• At the first study visit, participants will have an initial measurement of stomach acid production (gastric acid analysis) and an upper endoscopy to collect biopsies of esophagus, stomach, and small intestine tissue. Participants will receive YF476 to take by mouth once per day with food, and will be asked to keep a diary of medication doses, changes in symptoms, and any possible new symptoms or problems.

• After 3 weeks, participants will have another study visit with a physical examination, blood and urine tests, and questions about current condition and any side effects.

• After another 3 weeks (6 weeks after starting YF476), participants will have another gastric acid analysis and an upper endoscopy with biopsies. Participants may be eligible to receive a higher dose of YF476 if the endoscopy and biopsies show no significant change (decreased size and/or number of carcinoids or precancerous cells). If the stomach is completely normal at this visit on endoscopy and biopsy, participants will stop taking the study drug.

• After another 6 weeks (12 weeks after starting YF476), participants will have another physical examination, blood and urine tests, and an upper endoscopy with biopsies. YF476 will be stopped. Participants who show improvement after treatment will have a final followup visit. Participants who do not show improvement will not have the followup visit, but may be asked to return for additional clinic visits to check for side effects from YF476.

• The final visit will be a followup visit 12 weeks after the end of treatment with YF476. Participants who responded to YF476 will have blood tests and an upper endoscopy with biopsies.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 2017
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

• 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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoid
• Carcinoid Tumor
• Gastrinoma
• Zollinger-Ellison Syndrome

Intervention

Drug:
• YF476

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Ahlman H, Kölby L, Lundell L, Olbe L, Wängberg B, Granérus G, Grimelius L, Nilsson O. Clinical management of gastric carcinoid tumors. Digestion. 1994;55 Suppl 3:77-85. — View Citation

Aihara T, Fujishita T, Kanatani K, Furutani K, Nakamura E, Taketo MM, Matsui M, Chen D, Okabe S. Impaired gastric secretion and lack of trophic responses to hypergastrinemia in M3 muscarinic receptor knockout mice. Gastroenterology. 2003 Dec;125(6):1774-84. — View Citation

Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results from the American Society for Gastrointestinal Endoscopy/U.S. Food and Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy. Gastrointest Endosc. 1991 Jul-Aug;37(4):421-7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		4.5 years	No
Secondary	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])		4.5 years	No

External Links

•   NIH Clinical Center Detailed Web Page