YF476 in Barrett's Esophagus
Study Details
Study Description
Brief Summary
A phase 2, randomised, double-blind, out-patient trial to determine if YF476 is a safe and effective treatment in patients with Barrett's esophagus.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment Patients will take 25 mg YF476 once daily for 12 weeks |
Drug: YF476
gastrin receptor antagonist
Other Names:
|
| Placebo Comparator: YF476 Placebo Patients will take matching placebo once daily for 12 weeks |
Drug: YF476 placebo
placebo
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in Ki67 Biomarker Expression [Baseline and Week 12]
Esophagogastroduodenoscopy (EGD) was performed to enable taking biopsies for assessment of Ki67 expression, a marker of cellular proliferation. Ki67 expression was assessed by immunohistochemistry and calculating the number of Ki67 positive cells per mm^2 of Barrett's epithelium.
Secondary Outcome Measures
- Expression of Biomarkers Potentially Associated With Esophageal Adenocarcinoma (EAC) [Week 12]
Blood samples were taken for assay of biomarkers associated with esophageal adenocarcinoma. Changes in biomarker expression were derived from RNA-Sequencing and calculated as log-fold change comparing the treatment group to the placebo group. The nature of how results are derived by RNA-sequencing means summary statistics cannot be generated individually for each arm and a value has not been calculated for each individual participant. Therefore, results are reported as the relative change in biomarker expression in the treatment arm compared to the placebo arm.
- Abundance of Biomarkers of Gastric Acid Suppression [Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment)]
Blood samples were taken to assess the effects of YF476 on fasting serum gastrin, a marker of gastric acid suppression
- Abundance of Biomarkers of ECL Cell Hyperplasia [Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment)]
Blood samples were taken to assess the effects of YF476 on fasting plasma CgA, a marker of ECL cell hyperplasia
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Aged >18 years, with histologically confirmed diagnosis of Barrett's esophagus (BE) without dysplasia. A prior endoscopy with biopsies read as indefinite for dysplasia is permitted if biopsies from the most recent endoscopy prior to study entry demonstrated BE without dysplasia.
-
Minimum of 1 cm circumferential Barrett's mucosa on endoscopy or at least 2 cm maximal contiguous extent of Barrett's mucosa, as measured from the top of the gastric folds to the squamocolumnar junction (Prague criteria C>1, any M or any C, M>2).
-
Proton pump inhibitor use at least once daily, for at least 12 months prior to enrolment, and stable dose of PPI for the 3 months before enrolment. Any PPI, dose, and frequency allowable.
-
ECOG performance status <2 and Karnofsky >60%
-
Normal organ and marrow function, defined as white blood cells >3 x 10e9, absolute neutrophil count >1.5 x 10e9, platelets >100 x 10e9, creatinine <1.5 mg/dL, total bilirubin <1.5 mg/dL, AST <100 U/L, ALT <100 U/L.
-
Use of adequate contraception during the study, as follows;
-
Post-menopausal women must have had their last menstrual period at least 1 year ago.
-
Pre-menopausal women, who are sexually-active, must have had a hysterectomy or bilateral oophorectomy; or must use an intrauterine device (IUD), or spermicide with a diaphragm, cap or condom. Streroid contraceptives such as 'the pill' are not allowed unless in combination with one of the aforementioned barrier contraceptive methods.
-
Men must use a condom and spermicide.
-
Willingness to comply with all treatment and follow-up procedures.
-
Ability to understand and the willingness to sign a written informed consent document.
-
Up to date with all age-appropriate cancer screening tests, as per American Cancer Society guidelines, (Columbia University only), and no cancer screening tests planned for the next 21 weeks.
Exclusion Criteria:
-
Histologically confirmed BE with high-grade dysplasia.
-
Histologically confirmed diagnosis of invasive carcinoma of the esophagus.
-
Histologically confirmed BE with low-grade dysplasia that has been diagnosed by at least 2 expert gastrointestinal pathologists.
-
Prior endoscopic therapy for BE.
-
Any history of esophageal or gastric surgery.
-
History of atrophic gastritis, pernicious anemia, or Zollinger-Ellison syndrome.
-
Participation in a trial of an IMP within the previous 28 days.
-
Prolonged QTc interval >450 msec.
-
History of allergic reactions attributed to compounds of similar chemical composition of YF476.
-
History of baseline findings of:
-
diabetes mellitus requiring insulin therapy
-
pancreatitis (baseline amylase and/or lipase >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
-
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; active systemic infection; or psychiatric illness/social situations that would limit compliance with study requirements.
-
Certain medicines and herbal remedies taken during the 7 days before the start of the study drug.
-
A history of cancer >3 years from the time of enrolment, and the patient is not up to date with surveillance for that cancer (based on the American Cancer Society guidelines, Columbia University only), has evidence of cancer at the time of enrolment, or has surveillance tests planned within 21 weeks after enrolment.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Columbia University, Division of Digestive & Liver Diseases | New York | New York | United States | 10032 |
| 2 | MRC Cancer Unit, University of Cambridge | Cambridge | Cambridgeshire | United Kingdom | CB2 0XZ |
Sponsors and Collaborators
- Trio Medicines Ltd.
- Columbia University
- University of Cambridge
Investigators
- Principal Investigator: Julian A Abrams, MD MS, Columbia University
Study Documents (Full-Text)
More Information
Publications
None provided.- T-016
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Three patients were enrolled but failed screening due to elevated lipase, prolonged QTc or being diagnosed with lymphoma. |
| Arm/Group Title | Treatment | YF476 Placebo |
|---|---|---|
| Arm/Group Description | Patients will take 25 mg YF476 once daily for 12 weeks YF476: gastrin receptor antagonist | Patients will take matching placebo once daily for 12 weeks YF476 placebo: placebo |
| Period Title: Overall Study | ||
| STARTED | 13 | 11 |
| COMPLETED | 10 | 10 |
| NOT COMPLETED | 3 | 1 |
Baseline Characteristics
| Arm/Group Title | Treatment | YF476 Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Patients will take 25 mg YF476 once daily for 12 weeks YF476: gastrin receptor antagonist | Patients will take matching placebo once daily for 12 weeks YF476 placebo: placebo | Total of all reporting groups |
| Overall Participants | 13 | 11 | 24 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
4
30.8%
|
2
18.2%
|
6
25%
|
| >=65 years |
9
69.2%
|
9
81.8%
|
18
75%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
2
15.4%
|
1
9.1%
|
3
12.5%
|
| Male |
11
84.6%
|
10
90.9%
|
21
87.5%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| White |
13
100%
|
11
100%
|
24
100%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
7
53.8%
|
5
45.5%
|
12
50%
|
| United Kingdom |
6
46.2%
|
6
54.5%
|
12
50%
|
| Ki67 expression (cells/mm^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [cells/mm^2] |
1539
(514)
|
1556
(622)
|
1548
(559)
|
| Fasting serum gastrin concentration (marker of gastric acid suppression) (pmol/L) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [pmol/L] |
66.74
(41.736)
|
51.85
(29.104)
|
56.45
(35.997)
|
| Fasting plasma CgA concentration (marker of ECL cell hyperplasia) (nmol/L) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [nmol/L] |
12.93
(17.210)
|
9.12
(4.98)
|
11.18
(13.00)
|
Outcome Measures
| Title | Change in Ki67 Biomarker Expression |
|---|---|
| Description | Esophagogastroduodenoscopy (EGD) was performed to enable taking biopsies for assessment of Ki67 expression, a marker of cellular proliferation. Ki67 expression was assessed by immunohistochemistry and calculating the number of Ki67 positive cells per mm^2 of Barrett's epithelium. |
| Time Frame | Baseline and Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 3 patients in the treatment arm and 1 patient in the placebo arm were withdrawn from the study due to reasons unrelated to the treatment. Therefore, Week 12 data show results from 10 patients per arm. |
| Arm/Group Title | Treatment | YF476 Placebo |
|---|---|---|
| Arm/Group Description | Patients will take 25 mg YF476 once daily for 12 weeks YF476: gastrin receptor antagonist | Patients will take matching placebo once daily for 12 weeks YF476 placebo: placebo |
| Measure Participants | 13 | 11 |
| Baseline |
1539
(514)
|
1556
(622)
|
| Week 12 |
1575
(620.7)
|
1864
(640.3)
|
| Title | Expression of Biomarkers Potentially Associated With Esophageal Adenocarcinoma (EAC) |
|---|---|
| Description | Blood samples were taken for assay of biomarkers associated with esophageal adenocarcinoma. Changes in biomarker expression were derived from RNA-Sequencing and calculated as log-fold change comparing the treatment group to the placebo group. The nature of how results are derived by RNA-sequencing means summary statistics cannot be generated individually for each arm and a value has not been calculated for each individual participant. Therefore, results are reported as the relative change in biomarker expression in the treatment arm compared to the placebo arm. |
| Time Frame | Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 3 patients in the treatment arm were withdrawn from the study due to reasons unrelated to the treatment. Therefore, results are reported for 10 patients. |
| Arm/Group Title | Treatment |
|---|---|
| Arm/Group Description | Patients will take 25 mg YF476 once daily for 12 weeks YF476: gastrin receptor antagonist |
| Measure Participants | 10 |
| CCK2R, Week 12 |
-1.19
|
| PTGS2, Week 12 |
0.31
|
| DCLK1, Week 12 |
-0.34
|
| Title | Abundance of Biomarkers of Gastric Acid Suppression |
|---|---|
| Description | Blood samples were taken to assess the effects of YF476 on fasting serum gastrin, a marker of gastric acid suppression |
| Time Frame | Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment) |
Outcome Measure Data
| Analysis Population Description |
|---|
| After 6 patients (3 per treatment) had their Week 4 and 8 visits, the protocol was amended so that those visits were replaced by a single visit at Week 6 in order to reduce the total number of visits. |
| Arm/Group Title | Treatment | YF476 Placebo |
|---|---|---|
| Arm/Group Description | Patients will take 25 mg YF476 once daily for 12 weeks YF476: gastrin receptor antagonist | Patients will take matching placebo once daily for 12 weeks YF476 placebo: placebo |
| Measure Participants | 10 | 10 |
| Week 4 |
242.6
(142.3)
|
43.6
(9.9)
|
| Week 6 |
103.3
(89.9)
|
63.9
(32.2)
|
| Week 8 |
234.3
(156.5)
|
96.4
(54.2)
|
| Week 12 |
146.8
(112.8)
|
49.2
(20.4)
|
| Follow-up |
94.9
(78.8)
|
64.7
(37.7)
|
| Title | Abundance of Biomarkers of ECL Cell Hyperplasia |
|---|---|
| Description | Blood samples were taken to assess the effects of YF476 on fasting plasma CgA, a marker of ECL cell hyperplasia |
| Time Frame | Week 4, Week 6, Week 8, Week 12 and Follow-up (4 weeks after stopping YF476 treatment) |
Outcome Measure Data
| Analysis Population Description |
|---|
| After 6 patients (3 per treatment) had their Week 4 and 8 visits, the protocol was amended so that those visits were replaced by a single visit at Week 6 in order to reduce the total number of visits. |
| Arm/Group Title | Treatment | YF476 Placebo |
|---|---|---|
| Arm/Group Description | Patients will take 25 mg YF476 once daily for 12 weeks YF476: gastrin receptor antagonist | Patients will take matching placebo once daily for 12 weeks YF476 placebo: placebo |
| Measure Participants | 10 | 10 |
| Week 4 |
3.9
(1.8)
|
8.8
(3.7)
|
| Week 6 |
1.8
(0.9)
|
16.9
(9.8)
|
| Week 8 |
3.8
(1.8)
|
10.9
(6.0)
|
| Week 12 |
2.9
(2.5)
|
10.6
(7.4)
|
| Follow-up |
19.8
(26.1)
|
11.9
(7.2)
|
Adverse Events
| Time Frame | 16 weeks | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Any untoward medical occurrence in a study participant that does not necessarily have a causal relationship with the treatment | |||
| Arm/Group Title | Treatment | YF476 Placebo | ||
| Arm/Group Description | Patients will take 25 mg YF476 once daily for 12 weeks YF476: gastrin receptor antagonist | Patients will take matching placebo once daily for 12 weeks YF476 placebo: placebo | ||
All Cause Mortality |
||||
| Treatment | YF476 Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/13 (0%) | 0/11 (0%) | ||
Serious Adverse Events |
||||
| Treatment | YF476 Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/13 (7.7%) | 0/11 (0%) | ||
| Infections and infestations | ||||
| Scrotal abscess | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| Treatment | YF476 Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 13/13 (100%) | 11/11 (100%) | ||
| Cardiac disorders | ||||
| Bundle branch block right | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Gastrointestinal disorders | ||||
| Constipation | 2/13 (15.4%) | 2 | 1/11 (9.1%) | 1 |
| Diarrhoea | 2/13 (15.4%) | 3 | 1/11 (9.1%) | 1 |
| Abdominal pain | 1/13 (7.7%) | 1 | 1/11 (9.1%) | 1 |
| Nausea | 1/13 (7.7%) | 1 | 1/11 (9.1%) | 1 |
| Rectal haemorrhage | 1/13 (7.7%) | 1 | 1/11 (9.1%) | 1 |
| Abdominal distension | 0/13 (0%) | 0 | 1/11 (9.1%) | 1 |
| Abdominal upper pain | 0/13 (0%) | 0 | 1/11 (9.1%) | 2 |
| Dyspepsia | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Gatrooesophageal reflux disease | 0/13 (0%) | 0 | 1/11 (9.1%) | 1 |
| Mouth ulveration | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Vomiting | 0/13 (0%) | 0 | 1/11 (9.1%) | 1 |
| General disorders | ||||
| Chest pain | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Fatigue | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Pyrexia | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Infections and infestations | ||||
| Nasopharyngitis | 1/13 (7.7%) | 1 | 1/11 (9.1%) | 1 |
| Rash pustular | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Metabolism and nutrition disorders | ||||
| Hypoglycemia | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Myalgia | 0/13 (0%) | 0 | 2/11 (18.2%) | 2 |
| Arthralgia | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Nervous system disorders | ||||
| Headache | 3/13 (23.1%) | 3 | 3/11 (27.3%) | 3 |
| Presyncope | 1/13 (7.7%) | 1 | 1/11 (9.1%) | 1 |
| Dizziness | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 0/13 (0%) | 0 | 2/11 (18.2%) | 3 |
| Oropharyngeal pain | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Rhintis allergic | 0/13 (0%) | 0 | 1/11 (9.1%) | 1 |
| Epistaxis | 0/13 (0%) | 0 | 1/11 (9.1%) | 2 |
| Skin and subcutaneous tissue disorders | ||||
| Dermatitis acneiform | 1/13 (7.7%) | 1 | 0/11 (0%) | 0 |
| Rash | 0/13 (0%) | 0 | 1/11 (9.1%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr Malcolm Boyce |
|---|---|
| Organization | Trio Medicines Ltd |
| Phone | +44 20 8961 4130 |
| mboyce@triomedicines.com |
- T-016