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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

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ClinicalTrials.gov Identifier: NCT04535414
Recruitment Status : Not yet recruiting
First Posted : September 2, 2020
Last Update Posted : February 24, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.

...


Condition or disease Intervention/treatment Phase
Gastric Cancer Gastric Neoplasms Gastric Adenocarcinoma Device: Cellvizio (Registered trademark) 100 microscope Device: Olympus GIF 180 endoscope Phase 2

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 greater than or equal to18 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 350 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Phase II Randomized Trial of Bethesda Protocol Compared to Cambridge Method for Detection of Early Stage Gastric Cancer in CDH1 Mutation Carriers
Estimated Study Start Date : March 1, 2021
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/Arm 1
Bethesda protocol (investigational)
Device: Olympus GIF 180 endoscope
Participants will undergo white light endoscopy. The mucosa of the stomach will be thoroughly washed before examination and inspection will include repeated inflation and deflation to check distensibility and any abnormal appearing areas will additionally be biopsied. Non-targeted biopsies will be obtained as indicated per the assigned Arm.

Active Comparator: 2/Arm 2
Cambridge method (control) with confocal endomicroscopy
Device: Cellvizio (Registered trademark) 100 microscope
Subjects in Arm 2 will additionally undergo confocal imaging with contrast following the Cambridge method.

Device: Olympus GIF 180 endoscope
Participants will undergo white light endoscopy. The mucosa of the stomach will be thoroughly washed before examination and inspection will include repeated inflation and deflation to check distensibility and any abnormal appearing areas will additionally be biopsied. Non-targeted biopsies will be obtained as indicated per the assigned Arm.




Primary Outcome Measures :
  1. Determine if Bethesda protocol provides improved sensitivity for detection of early stage gastric cancer in CDH1 germline mutation carriers compared to the Cambridge method [ Time Frame: 14 days ]
    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.


Secondary Outcome Measures :
  1. Define the false negative rate of SRCC detection using Bethesda protocol and Cambridge methods in patients who proceed to risk-reducing total gastrectomy [ Time Frame: 14 days ]
    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.

  2. To estimate and compare the difference in crude cancer detection rates between endoscopy using the Bethesda protocol and the Cambridge method [ Time Frame: 14 days ]
    The difference in fractions of SRCCs which are found on endoscopy by the two methods.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Initial Enrollment:

-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:

  • Known bleeding disorder or thrombocytopenia that is a contraindication 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04535414


Contacts
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Contact: Rebecca S Trupp, R.N. (240) 858-3610 rebecca.trupp@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jeremy L Davis, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04535414    
Other Study ID Numbers: 200150
20-C-0150
First Posted: September 2, 2020    Key Record Dates
Last Update Posted: February 24, 2021
Last Verified: January 25, 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Diagnostic
Diagnosis
HDGC
SRCC
Confocal Endoscopic Microscopy (CEM)
Additional relevant MeSH terms:
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Stomach Neoplasms
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases