Phase II Randomized Trial of Bethesda Protocol Compared to Cambridge Method for Detection of Early Stage Gastric Cancer in CDH1 Mutation Carriers

Study Overview
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Brief Summary
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Background: Some people have a mutation in the CDH1 gene that is known to lead to stomach cancer. They are advised to get regular endoscopies with biopsies even if their stomach appears normal. The endoscopy method currently used is called the 'Cambridge Method.' Researchers want to test a new method called the 'Bethesda Protocol.' Objective: To compare the Cambridge Method and Bethesda Protocol and find out which is more efficient in catching early signs of cancer. Eligibility: Adults age 18 and older who have a mutation in the CDH1 gene. Design: Participants will be screened with a review of their medical history, medical records, and physical status. Participants will be put into group 1 (Bethesda Protocol) or group 2 (Cambridge Method). Participants will have a physical exam. They will have endoscopy. For this, they will be put under general anesthesia. They will wear compression cuffs around their legs to prevent blood clots. A lighted tube will be inserted into their mouth and go down to their stomach. For group 1 participants, 88 pieces of tissue will be taken from 22 areas of their stomach. For group 2 participants, 30 pieces of tissue will be taken from 6 areas of their stomach. Then group 2 will be injected with a contrast dye. A microscope will be inserted, and more samples will be taken. About 14 days later, participants will have a follow-up visit or phone call. They may give stool samples every 3 to 6 months for 12 months for research purposes. Participants may have another endoscopy 6-18 months later.

Detailed Description
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Background: Hereditary Diffuse Gastric Cancer (HDGC) is most often attributed to inactivating germline mutations in the E-cadherin (CDH1) tumor suppressor gene. Mutation carriers have a 24-70% lifetime risk of developing gastric adenocarcinoma. International consensus guidelines recommend endoscopic screening and surveillance of CDH1 mutation carriers who decline risk-reducing total gastrectomy (TG). However, this approach lacks sufficient sensitivity for detection of occult, intramucosal foci of signet ring cancer cells (SRCC), which are pathognomonic of HDGC. Our team has established a systematic endoscopic screening protocol (Bethesda protocol) that demonstrates a higher rate of SRCC detection compared to historic controls using the currently recommended Cambridge method. Objective: Determine if Bethesda protocol provides improved sensitivity for detection of early-stage gastric cancer in CDH1 germline mutation carriers compared to the Cambridge method. Eligibility: Subjects with pathogenic or likely pathogenic CDH1 germline mutation. Age >=18 years. Physiologically able to undergo upper endoscopy Design: Phase II randomized study to compare Bethesda protocol and Cambridge method for detection of intramucosal SRCC in asymptomatic CDH1 mutation carriers undergoing endoscopic screening or surveillance.

Official Title
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Phase II Randomized Trial of Bethesda Protocol Compared to Cambridge Method for Detection of Early Stage Gastric Cancer in CDH1 Mutation Carriers

Conditions
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Gastric Cancer, Gastric Neoplasms, Gastric Adenocarcinoma

Intervention / Treatment
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* Device: Cellvizio (Registered trademark)Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes
* Device: Olympus GIF 190 endoscope


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: An individual who harbors a pathogenic, or likely pathogenic, CDH1 germline variant. Note: individuals with CDH1 variant classified as any of the following are not eligible: variant of uncertain significance benign likely benign. Age greater than or equal to 18 years. Physiologically able to undergo upper endoscopy. Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Any clinical contraindication (e.g., known bleeding disorder, thrombocytopenia) to endoscopic biopsy. Unstable angina or recent (within 3 months) myocardial infarction. Any clinical contraindication to general anesthesia. Re-Enrollment: INCLUSION CRITERIA: Subject must have previously been enrolled on the study and must have undergone endoscopy. Note: Subject may re-enroll only once after initial endoscopy performed Subject must have clinical need for a repeat endoscopy Prior on-protocol endoscopy must have occurred at least 6 months (+/- 2 weeks) and no greater than 18 months (+/- 4 weeks)

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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/ Arm 1<br>Bethesda protocol (investigational)with confocal endomicroscopy in assigned participants | Device: Cellvizio (Registered trademark)Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes<br>* Participants of both study arms will undergo confocal endomicroscopy of the gastric mucosa until sufficient data for statistically accurate and reliable application of machine learning (i.e., computer models), currently believed to total the first 50 enrolled participants.<br>Device: Olympus GIF 190 endoscope<br>* Participants will undergo white light endoscopy. The mucosa of the stomach may be thoroughly washed before examination, as medically indicated, and inspection will include repeated inflation and deflation to check distensibility and any abnormal appearing areas will additionally be biopsied. Nontargeted biopsies will be obtained as indicated per the assigned Arm.<br>|
| Active Comparator: 2/ Arm 2<br>Cambridge method (control) with confocal endomicroscopy in assigned participants | Device: Cellvizio (Registered trademark)Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes<br>* Participants of both study arms will undergo confocal endomicroscopy of the gastric mucosa until sufficient data for statistically accurate and reliable application of machine learning (i.e., computer models), currently believed to total the first 50 enrolled participants.<br>Device: Olympus GIF 190 endoscope<br>* Participants will undergo white light endoscopy. The mucosa of the stomach may be thoroughly washed before examination, as medically indicated, and inspection will include repeated inflation and deflation to check distensibility and any abnormal appearing areas will additionally be biopsied. Nontargeted biopsies will be obtained as indicated per the assigned Arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine if Bethesda protocol provides improved sensitivity for detection of early stage gastric cancer in CDH1 germline mutation carriers compared to the Cambridge method | Among patients who undergo gastrectomy, in each of the two arms, the fraction of patients who had SRCCs previously identified by endoscopic biopsy out of those who had SRCCs detected on final pathologic analysis of gastrectomy explants will be used to determine the sensitivity of each arm. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Define the false negative rate of SRCC detection using Bethesda protocol and Cambridge methods in patients who proceed to risk-reducing total gastrectomy | In patients who choose to undergo total gastrectomy in each of the two arms, the fraction of patients who had SRCC identified on final pathology but were negative for SRCC on EGD will yield the false negative biopsy rate. | 14 days | 
| To estimate and compare the difference in crude cancer detection rates between endoscopy using the Bethesda protocol and the Cambridge method | The difference in fractions of SRCCs which are found on endoscopy by the two methods. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HDGC, Diagnostic, Diagnosis, SRCC, Confocal Endoscopic Microscopy (CEM)