Gastric CancerPhase 2NCT04535414
Phase II Randomized Trial of Bethesda Protocol Compared to Cambridge Method for Detection of Early Stage Gastric Cancer in CDH1 Mutation Carriers
A Phase 2 study testing Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes, Olympus Graphics Interchange Format (GIF) 190 endoscope and Gastric mucosal biopsy in people with Gastric Cancer and Gastric Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Gastric Cancer, Gastric Neoplasms, Gastric Adenocarcinoma
- What is being tested?
- Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes, Olympus Graphics Interchange Format (GIF) 190 endoscope and Gastric mucosal biopsy
- Type of treatment
- Medical device, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 195 participants
- Where
- 1 siteUnited States
- Study dates
- 22 Jun 2023to 10 Jan 2025
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 11Show fewer
- 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)
Who cannot join
- 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:
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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.'
Read more
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.
Read the 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
- Being tested
- Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes, Olympus Graphics Interchange Format (GIF) 190 endoscope, Gastric mucosal biopsy
- Keywords
- Diagnostic, Diagnosis, HDGC, SRCC, Confocal Endoscopic Microscopy (CEM)
- Medical subject headings
- Stomach Neoplasms, Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal MiniprobesDevice
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 endoscopeDevice
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 biopsyProcedure or surgery
As clinically indicated.
| Study group | Role | What they receive |
|---|---|---|
| 1/ Arm 1: Bethesda Protocol (investigational) with Confocal Endomicroscopy | Experimental | Bethesda protocol (investigational) with confocal endomicroscopy in assigned participants Receives: Device: Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes; Device: Olympus Graphics Interchange Format (GIF) 190 endoscope; Procedure: Gastric mucosal biopsy |
| 2/ Arm 2: Cambridge Method (control) with Confocal Endomicroscopy | Active comparator | Cambridge method (control) with confocal endomicroscopy in assigned participants Receives: Device: Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes; Device: Olympus Graphics Interchange Format (GIF) 190 endoscope; Procedure: Gastric mucosal biopsy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of Participants With Improved Sensitivity for Detection of Early-stage Gastric Cancer in CDH1 Germline Mutation Carriers Compared to the Cambridge Method
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.
Measured: 14 days
Secondary outcomes (2)
Proportion of Participants Who Had Signet Ring Cell Carcinoma (SRCC) Identified on Final Pathology But Were Negative for SRCC on Esophagogastroduodenoscopy (EGD)
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.
Measured: 14 days
Difference in Fractions of Participants Crude Cancer Detection Rates Between Endoscopy Using the Bethesda Protocol and the Cambridge Method
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.
Measured: 14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Sep 2020
- Study start22 Jun 2023
- Primary completion12 Sep 2024
- Study completion10 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Gastric CancerStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 195 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Andrew Blakely, National Cancer Institute (NCI)
- Investigators
- Andrew Blakely, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04535414
- Sponsor's protocol ID
- 200150
- Other IDs
- 20-C-0150
- Status last verified
- Jan 2025
- First submitted
- 1 Sep 2020
- Last updated
- 17 Jan 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- Yes: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, bacterial gene sequences will be deposited in GenBank.
Study at a glance
From the registry record, last updated by the sponsor on 17 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Randomized Trial of Bethesda Protocol Compared to Cambridge Method for Detection of Early Stage Gastric Cancer in CDH1 Mutation Carriers
- ClinicalTrials.gov ID
- NCT04535414
- Acronym / sponsor ID
- 200150
- Conditions
- Gastric Cancer, Gastric Neoplasms, Gastric Adenocarcinoma
- Keywords
- Diagnostic, Diagnosis, HDGC, SRCC, Confocal Endoscopic Microscopy (CEM)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 195 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 22 Jun 2023 (actual)
- Primary completion
- 12 Sep 2024 (actual)
- Study completion
- 10 Jan 2025 (actual)
- First posted
- 2 Sep 2020 (actual)
- Results
- Posted 17 Jan 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1/ Arm 1: Bethesda Protocol (investigational) with Confocal Endomicroscopy | Experimental | Device: Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes, Device: Olympus Graphics Interchange Format (GIF) 190 endoscope, Procedure: Gastric mucosal biopsyBethesda protocol (investigational) with confocal endomicroscopy in assigned participants |
| 2/ Arm 2: Cambridge Method (control) with Confocal Endomicroscopy | Active comparator | Device: Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes, Device: Olympus Graphics Interchange Format (GIF) 190 endoscope, Procedure: Gastric mucosal biopsyCambridge method (control) with confocal endomicroscopy in assigned participants |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- An individual who harbors a pathogenic, or likely pathogenic, cadherin-1 gene (CDH1) germline variant.
- variant of uncertain significance
- benign
- likely benign.
- 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
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal MiniprobesParticipants 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. | Device | 1/ Arm 1: Bethesda Protocol (investigational) with Confocal Endomicroscopy, 2/ Arm 2: Cambridge Method (control) with Confocal Endomicroscopy |
| Olympus Graphics Interchange Format (GIF) 190 endoscopeParticipants 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. | Device | 1/ Arm 1: Bethesda Protocol (investigational) with Confocal Endomicroscopy, 2/ Arm 2: Cambridge Method (control) with Confocal Endomicroscopy |
| Gastric mucosal biopsyAs clinically indicated. | Procedure or surgery | 1/ Arm 1: Bethesda Protocol (investigational) with Confocal Endomicroscopy, 2/ Arm 2: Cambridge Method (control) with Confocal Endomicroscopy |
Primary outcome
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.
2 secondary outcomes
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
Difference in Fractions of Participants Crude Cancer Detection Rates Between Endoscopy Using the Bethesda Protocol and the Cambridge Method
Time frame: 14 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jan 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, bacterial gene sequences will be deposited in GenBank.
Related trials for Gastric Cancer
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingPhase 2/3
Multicenter Validation Trial of [18F]AlF-FAPI-74 for PET Imaging of Cancer-associated Fibroblasts Through Fibroblast Activation Protein Inhibitors (FAPI) in Different Tumor Types
Oesophageal Cancer, Gastric Cancer
Not yet recruitingPhase 1
GK01 Cell Therapy in Gastric Cancer With Peritoneal Metastasis
Gastric Cancer (GC)
RecruitingPhase 3
A Study of Neoadjuvant-adjuvant Durvalumab and FLOT Chemotherapy Followed by Adjuvant Durvalumab in Chinese Patients With Resectable GC/GEJC.
Gastric, Esophagogastric Junction
Active, not recruitingEarly Phase 1
Iomab-ACT: A Pilot Study of 131-I Apamistamab Followed by CD19-Targeted CAR T-Cell Therapy for Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma
B-ALL, DLBCL
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrew Blakely, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cellvizio (Registered trademark) Real-Time In Vivo Cellular Imaging Platform with Confocal Miniprobes, Olympus Graphics Interchange Format (GIF) 190 endoscope and Gastric mucosal biopsy in people with Gastric Cancer and Gastric Neoplasms, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jan 2025.