YF476 and Type II Gastric Carcinoids

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

This study will evaluate whether treatment with YF476 is safe and effective in reducing the size of type II gastric carcinoid tumours, or limiting the abnormal growth of gastric ECL cells, in patients with Zollinger-Ellison syndrome.

Study Overview

• Status: Terminated
• Conditions: Zollinger-Ellison Syndrome
• Intervention / Treatment: Drug: YF476

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Men; post-menopausal women; pre-menopausal women who have been sterilised by tubal ligation, hysterectomy or bilateral oophorectomy; or pre-menopausal women using one of the allowed methods of contraception: condom and spermicide or intra-uterine device.
2. Patients with serum gastrin >250 pg/mL.
3. Hepatic function: AST and ALT ≤2.0 x ULN; total bilirubin ≤1.0 x ULN.
4. Renal function: serum creatinine <1.0 x ULN.
5. Haematologic function: Hb ≥10.0 g/dL; WBC ≥3.5 x 10e9 /L; ANC ≥1.5 x 10e9 /L; platelets ≥100 x 10e9 /L.
6. Coagulation parameters: INR or PT ≤1.0 x ULN; PTT ≤1.0 x ULN.
7. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial.
8. 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 >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 1 diabetes mellitus;
    • pancreatitis (baseline amylase and/or >2.0 x ULN);
    • hepatitis B, hepatitis C or HIV;
    • malabsorption syndrome or inability to swallow or retain oral medicine;
    • major surgery <28 days prior to enrolment;
    • ECOG performance status >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 <1 month); respiratory disease (advanced COPD or pulmonary fibrosis); uncontrolled hypertension; or active systemic infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eligible patients; The dose will be 100 mg YF476 once daily. When 6 patients have completed 12 weeks' treatment with that dose, it may be increased to 150 or 200 mg once daily. Patients will have type II gastric carcinoids and/or ECL cell hyperplasia/dysplasia.	Drug: YF476; Gastrin receptor antagonist; Other Names: Netazepide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regression of Gastric Carcinoids and/or ECL Cell Hyperplasia Defined by Physical Measurements Taken During Endoscopy	Regression is defined as a 25% reduction in the size / number of endoscopically evident type II gastric carcinoids. For each participant, three gastric carcinoids were identified and measured at baseline. The same gastric carcinoids were then measured at the Week 12 visit and the percentage difference in size from baseline calculated. The mean percentage change of the three gastric carcinoids per participant is recorded.	Week 12 visit
A Reduction of 25% in the Gastric ECL Cell Density.	A reduction of 25% in the gastric ECL cell density.	Week 12 visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in Histological Grade of Gastric Carcinoids/ECL Cell Hyperplasia Defined by Physical Measurements Taken During Endoscopy	Reduction in the histological grade of the carcinoids/hyperplasia when compared to baseline.	Week 12 visit
Level of Chromogranin A (CgA) Biomarkers Measured in Blood Samples	The level of a key biomarker chromogranin A (CgA) that is circulating in the blood was measured.	Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)
Acid Control Study 1, Control of Gastric Acid Secretion Assessed by Changes in Drug-controlled Gastric Acid Analysis, Volume of Gastric Aspirate	Assessed by changes in drug-controlled gastric acid analysis. A nasogastric tube (NGT) was placed through one nare and into the stomach. Gastric secretions were suctioned and discarded at T = 0 and then aspirated for 1 h in 15 min increments to measure the control acid output. Patients who could not tolerate NGT placement had endoscopic gastric analysis (EGA) performed during upper endoscopy. During EGA, a single 10 - 15 min collection was aspirated under direct visualization. Patients 01 and 02 had acid measured via NGT, whereas Patient 03 had acid measured via EGA. At the Week 2 visit, the baseline acid control was measured. At the Week 6 visit, the acid control was measured after a dose of netazepide. Results are provided for three acid control measures: Volume of aspirate (mL); Acid in aspirate (mEq); Acid output (mEq)	Week 2 visit (baseline) and Week 6 visit
Decrease in ECL Cell-specific Products Assessed by Quantitative PCR	Assessed by quantitative PCR.	Week 2 visit (baseline), Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)
Improvement in Reflux/Dyspepsia Symptoms Using the Gastroesophageal Reflux Disease Health Related Quality of Life (GERD-HRQL) Instrument	Assessed by the Gastroesophageal Reflux Disease Health Related Quality of Life (GERD-HRQL) instrument. Patients assessed a total of 10 symptoms on a scale of 0-5 where: 0 = no symptoms; 1 = symptoms noticeable, but not bothersome; 2 = symptoms noticeable and bothersome, but not every day; 3 = symptoms bothersome everyday; 4 = symptoms affect daily activities; and 5 = symptoms are incapacitating (unable to do daily activities). The total score was summed and reported. The maximum obtainable total score was 50 and minimum obtainable total score was 0, with higher scores indicating a worse outcome and lower scores indicating a better outcome.	Week 2 visit (baseline), Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)
Safety and Tolerability	Assessed by monitoring adverse events reported by patients	Week 2 visit (baseline), Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)
Circulating Plasma Concentration of Gastrin	The level of gastrin biomarkers circulating in the blood was measured.	Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)
Acid Control Study 2, Control of Gastric Acid Secretion Assess by Changes in Drug-controlled Gastric Acid Analysis: Acid Content in Gastric Aspirate	Assessed by changes in drug-controlled gastric acid analysis. A nasogastric tube (NGT) was placed through one nare and into the stomach. Gastric secretions were suctioned and discarded at T = 0 and then aspirated for 1 h in 15 min increments to measure the control acid output. Patients who could not tolerate NGT placement had endoscopic gastric analysis (EGA) performed during upper endoscopy. During EGA, a single 10 - 15 min collection was aspirated under direct visualization. Patients 01 and 02 had acid measured via NGT, whereas Patient 03 had acid measured via EGA. At the Week 2 visit, the baseline acid control was measured. At the Week 6 visit, the acid control was measured after a dose of netazepide. Results are provided for three acid control measures: Volume of aspirate (mL); Acid in aspirate (mEq); Acid output (mEq)	Week 2 visit (baseline) and Week 6 visit
Acid Control Study 3, Control of Gastric Acid Secretion Assess by Changes in Drug-controlled Gastric Acid Analysis: Acid Output	Assessed by changes in drug-controlled gastric acid analysis. A nasogastric tube (NGT) was placed through one nare and into the stomach. Gastric secretions were suctioned and discarded at T = 0 and then aspirated for 1 h in 15 min increments to measure the control acid output. Patients who could not tolerate NGT placement had endoscopic gastric analysis (EGA) performed during upper endoscopy. During EGA, a single 10 - 15 min collection was aspirated under direct visualization. Patients 01 and 02 had acid measured via NGT, whereas Patient 03 had acid measured via EGA. At the Week 2 visit, the baseline acid control was measured. At the Week 6 visit, the acid control was measured after a dose of netazepide. Results are provided for three acid control measures: Volume of aspirate (mL); Acid in aspirate (mEq); Acid output (mEq)	Week 2 visit (baseline) and Week 6 visit

Collaborators and Investigators

• Sponsor: Trio Medicines Ltd.
• Collaborators: National Institutes of Health (NIH)

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2011
• Primary Completion (Actual): June 22, 2012
• Study Completion (Actual): June 22, 2012

Study Registration Dates

• First Submitted: May 13, 2015
• First Submitted That Met QC Criteria: May 21, 2015
• First Posted (Estimate): May 27, 2015

Study Record Updates

• Last Update Posted (Actual): January 29, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: YF476; Zollinger-Ellison syndrome; netazepide; gastric carcinoids
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Disease; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Intestinal Diseases; Peptic Ulcer; Duodenal Diseases; Pancreatic Diseases; Neuroendocrine Tumors; Paraneoplastic Syndromes; Pancreatic Neoplasms; Carcinoma, Islet Cell; Paraneoplastic Endocrine Syndromes; Syndrome; Carcinoid Tumor; Gastrinoma; Zollinger-Ellison Syndrome
• Other Study ID Numbers: T-010; 11-DK-0114 (Other Identifier: NIHR)