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

NCT ID: NCT04535414

Last Updated: 2025-01-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 195 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-22
• Study Completion Date: 2025-01-10

Brief Summary

Background:

Some people have a mutation in the cadherin-1 gene (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

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.

Conditions

Gastric Cancer; Gastric Neoplasms; Gastric Adenocarcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

1/ Arm 1: Bethesda Protocol (investigational) with Confocal Endomicroscopy

Bethesda protocol (investigational) with confocal endomicroscopy in assigned participants

Group Type: EXPERIMENTAL

Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes

Intervention Type: DEVICE

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.

Olympus Graphics Interchange Format (GIF) 190 endoscope

Intervention Type: DEVICE

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.

Gastric mucosal biopsy

Intervention Type: PROCEDURE

As clinically indicated.

2/ Arm 2: Cambridge Method (control) with Confocal Endomicroscopy

Cambridge method (control) with confocal endomicroscopy in assigned participants

Group Type: ACTIVE_COMPARATOR

Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes

Intervention Type: DEVICE

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.

Olympus Graphics Interchange Format (GIF) 190 endoscope

Intervention Type: DEVICE

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.

Gastric mucosal biopsy

Intervention Type: PROCEDURE

As clinically indicated.

Interventions

Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes

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.

Intervention Type: DEVICE

Olympus Graphics Interchange Format (GIF) 190 endoscope

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.

Intervention Type: DEVICE

Gastric mucosal biopsy

As clinically indicated.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• An individual who harbors a pathogenic, or likely pathogenic, cadherin-1 gene (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.

• 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)

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:

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Andrew Blakely

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrew Blakely, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

National Institutes of Health Clinical Center

Bethesda, Maryland, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Related Links

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2020-C-0150.html

NIH Clinical Center Detailed Web Page

Other Identifiers

20-C-0150

Identifier Type: -

Identifier Source: secondary_id

200150

Identifier Type: -

Identifier Source: org_study_id