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Protocol Details

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

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

11-DK-0114

Sponsoring Institute

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

Children

Special Instructions

Currently Not Provided

Keywords

Gastrin Antagonist;
Gastrin;
Zollinger-Ellison Syndrome;
Gastric Acid;
Gastric Carcinoid Tumors

Recruitment Keyword(s)

Zollinger-Ellison Syndrome;
ZES;
Gastric Tumors

Condition(s)

Carcinoid

Investigational Drug(s)

YF476

Investigational Device(s)

None

Intervention(s)

Drug: YF476

Supporting Site

National Institute of Diabetes and Digestive and Kidney Diseases

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.

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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. 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.


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Citations:

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.

Ahlman H, K(SqrRoot)(Delta)lby L, Lundell L, Olbe L, W(SqrRoot) ngberg B, Gran(SqrRoot)(Copyright)rus G, Grimelius L, Nilsson O. Clinical management of gastric carcinoid tumors. Digestion. 1994;55 Suppl 3:77-85.

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.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Stephen A. Wank, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
BG 10 RM 9C101
10 CENTER DR
BETHESDA MD 20814
(301) 496-4202
stevew@bdg10.niddk.nih.gov

Stephen A. Wank, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
BG 10 RM 9C101
10 CENTER DR
BETHESDA MD 20814
(301) 496-4202
stevew@bdg10.niddk.nih.gov

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

prpl@mail.cc.nih.gov

Clinical Trials Number:

NCT01322542

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