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Completed

NCT Number: NCT04535414

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

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.

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Key information

Conditions

Gastric Cancer Digestive System Diseases Digestive System Neoplasms Disease Gastric Adenocarcinoma Gastric Neoplasms Gastrointestinal Diseases Gastrointestinal Neoplasms Neoplasms Neoplasms by Site Pathologic Processes Pathological Conditions, Signs and Symptoms Stomach Diseases Stomach Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

  • 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.

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)

Treatment and study plan

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

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

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

Procedure

As clinically indicated.

Primary outcomes

  1. Proportion of Participants With Improved Sensitivity for Detection of Early-stage Gastric Cancer in CDH1 Germline Mutation Carriers Compared to the Cambridge Method

    Time frame: 14 days

    Among participants who undergo gastrectomy, in each of the two arms, the fraction of participants who had signet ring cell carcinoma (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 difference between 30% sensitivity in the Cambridge method and 60% sensitivity in the Bethesda protocol of each arm on a Fisher's exact test with a 0.05 two-sided significance level and reported with a 95% confidence interval.

Secondary outcomes

  1. Proportion of Participants Who Had Signet Ring Cell Carcinoma (SRCC) Identified on Final Pathology But Were Negative for SRCC on Esophagogastroduodenoscopy (EGD)

    Time frame: 14 days

    False negative rate of SRCC detection in participants who undergo risk-reducing total gastrectomy using the Bethesda protocol and Cambridge method. The differences in fractions will be compared using a two-tailed Fisher's exact test and reported with a 95% confidence interval.

  2. Difference in Fractions of Participants Crude Cancer Detection Rates Between Endoscopy Using the Bethesda Protocol and the Cambridge Method

    Time frame: 14 days

    The difference in fractions of participants with signet ring cell carcinoma (SRCCs) crude cancer detection rates found on endoscopy by the Bethesda protocol and the Cambridge method determined by the power to detect a difference with a two-sided 0.05 significance level between 15% and 30% crude cancer detection rates and reported with a 95% confidence interval.

Other outcomes

  1. Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

    Time frame: From the start of endoscopy through 14 days following study interventions, an average of 2 weeks

    Here is the number of participants with non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence.

Sponsors and collaborators

Lead sponsor

National Cancer Institute (NCI)

Nih

Registry information

Important dates

Study start
2023
Primary completion
2024
Study completion
2025
First posted
Sep 2, 2020
Registry last updated
Jan 17, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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