YF476 and Type II Gastric Carcinoids

Study Overview
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Brief Summary
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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.

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

Conditions
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Zollinger-Ellison Syndrome

Intervention / Treatment
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* Drug: YF476


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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. Patients with serum gastrin >250 pg/mL. Hepatic function: AST and ALT ≤2.0 x ULN; total bilirubin ≤1.0 x ULN. Renal function: serum creatinine <1.0 x ULN. Haematologic function: Hb ≥10.0 g/dL; WBC ≥3.5 x 10e9 /L; ANC ≥1.5 x 10e9 /L; platelets ≥100 x 10e9 /L. Coagulation parameters: INR or PT ≤1.0 x ULN; PTT ≤1.0 x ULN. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial. Willingness to give fully-informed, written consent. Exclusion criteria: Patients under 18 years. Women who are pregnant, lactating or using a steroid contraceptive. Prior gastric resection or bypass. Planned gastrinoma resection during the study period. Patients on somatostatin analogues, except for those on therapy for >6 months with stable or worsening carcinoids. Inability to tolerate endoscopy, or refusal of endoscopy. 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. Certain medicines and herbal remedies taken during the 7 days before visit 2. Participation in a trial of an IMP within the previous 28 days. Presence of drug or alcohol abuse. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eligible patients<br>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<br>* Gastrin receptor antagonist<br>* Other names: Netazepide;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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YF476, netazepide, gastric carcinoids, Zollinger-Ellison syndrome