Molecular Characterization of Tumor-Microenvironment Interactions to Predict Drug Resistance in Gastric and GEJ Adenocarcinoma (GASTROIMMUNE)

July 2, 2026 updated by: Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis

Molecular Characterization of Tumor-Microenvironment Interactions to Predict Drug Resistance to Perioperative Treatment in Patients With Gastric and Gastroesophageal Junction Adenocarcinoma

Surgical resection remains the only curative option for resectable gastric cancer, but perioperative FLOT chemotherapy is associated with substantial rates of chemoresistance and recurrence, largely driven by marked tumor heterogeneity. Recent data from the MATTERHORN phase III trial have shown that adding durvalumab to perioperative FLOT improves pathological complete response and survival, supporting this combination as a new standard of care for resectable gastric and gastroesophageal junction adenocarcinoma.

This observational multicenter study aims to characterize angiogenic and immune profiles within the tumor microenvironment and peripheral blood, in order to identify cellular and molecular signatures associated with response or resistance to perioperative FLOT plus durvalumab. Longitudinal biospecimen collection (PBMCs, serum, plasma, endoscopic biopsies, surgical specimens) will be integrated with multiparametric flow cytometry, single-cell transcriptomics and TCR/BCR sequencing, immunohistochemistry, pathomics and multiplex immunoassays, to provide mechanistic insights and potential predictive biomarkers.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

This observational multicenter study will prospectively enroll approximately 250 patients with operable, locally advanced gastric or gastroesophageal junction adenocarcinoma who receive perioperative FLOT plus durvalumab according to current clinical practice. Patients typically present with locally advanced disease (T ≥2 and/or node-positive) as defined by the AJCC 8th edition, and are candidates for perioperative chemo-immunotherapy followed by surgery.

Peripheral blood samples for PBMC isolation and serum/plasma storage will be obtained at baseline before neoadjuvant treatment (N1), before surgery (N2), and approximately 2 months after completion of adjuvant therapy (N3). Tumor tissue will be collected through diagnostic endoscopic biopsies and surgical resections; fresh and FFPE specimens will be used for immunohistochemistry, pathomics and omics analyses, including organoid cultures.

The study will implement a multiparametric registry integrating clinical, imaging and omics data, ensuring harmonized data collection across the two IRCCS centers (IRCCS Saverio de Bellis and Humanitas Clinical and Research Center). Tumor-infiltrating lymphocytes and PBMCs will be profiled by spectral flow cytometry (up to 40 markers), single-cell RNA sequencing and TCR/BCR sequencing to define immune subsets, activation and exhaustion states, and clonal expansion patterns.

Whole-slide digital histology (HE-stained sections) will be analyzed to derive robust pathomic biomarkers related to vascular architecture and immune cell distribution, previously associated with response to anti-angiogenic therapies; these biomarkers will be validated in the perioperative gastric/GEJ cohort. Serum cytokine and chemokine panels will be assessed using Luminex xMAP technology, while CT imaging acquired for staging and follow-up will be annotated to calibrate mathematical models predicting treatment response.

Statistical analyses will treat this project as a pilot study, given the lack of previous evidence on predictors of complete response to perioperative therapy. Patients will be stratified by Tumor Regression Grade (TRG), with TRG 1-2 considered responders and TRG 3-4 non-responders, and effect-size measures, ensemble machine-learning algorithms and multilevel longitudinal models will be used to identify and evaluate angiogenic and immune markers associated with short-term outcomes.

Study Type

Observational

Enrollment (Estimated)

250

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Adult patients (age >= 18 years) with histologically confirmed, operable, locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, candidate to perioperative treatment with FLOT plus durvalumab at the participating IRCCS centers. Patients are enrolled consecutively as they start perioperative treatment in clinical practice.

Description

Inclusion Criteria:

  1. Histologically confirmed adenocarcinoma of the stomach (gastric cancer, GC) or gastroesophageal junction (GEJ)
  2. Operable, locally advanced disease (T >= 2 and/or node-positive) according to AJCC 8th edition staging
  3. Candidate for perioperative chemotherapy with FLOT regimen combined with durvalumab, as per clinical practice
  4. Age >= 18 years
  5. Provision of written informed consent prior to any study-specific procedure

Exclusion Criteria:

  1. Presence of another active malignant disease
  2. Advanced or metastatic gastric/GEJ cancer not eligible for surgical treatment
  3. Inability or unwillingness to provide written informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Perioperative FLOT plus Durvalumab Cohort
Patients with operable, locally advanced gastric or gastroesophageal junction adenocarcinoma receiving perioperative chemotherapy (FLOT regimen: docetaxel, oxaliplatin, leucovorin, 5-fluorouracil) combined with durvalumab (anti-PD-L1) as standard of care. Longitudinal biological samples (peripheral blood and tumor tissue) are collected for molecular characterization of tumor-microenvironment interactions and identification of predictive biomarkers of pharmacological resistance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Identification of immune and angiogenic cellular subsets associated with pathological response to perioperative FLOT plus durvalumab
Time Frame: At surgical resection (approx. 3-4 months after treatment initiation) and approx. 2 months after completion of adjuvant therapy
Identification of specific cellular subsets and activation/exhaustion states, assessed by scRNA-seq, TCR/BCR sequencing, and multiparametric spectral flow cytometry of tumor-infiltrating lymphocytes (TILs) and PBMCs, associated with pathological response (Tumor Regression Grade TRG 1-2) or resistance (TRG 3-4) to perioperative FLOT plus durvalumab.
At surgical resection (approx. 3-4 months after treatment initiation) and approx. 2 months after completion of adjuvant therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Association between angiogenic and immune signatures and clinical outcomes
Time Frame: From baseline to approximately 2 months after completion of adjuvant therapy (up to approximately 9 months)
Correlation of angiogenic and immune profiles (serum cytokine/chemokine panels by Luminex xMAP, pathomic biomarkers from whole-slide HE images, and flow cytometry data) with clinical outcomes including Tumor Regression Grade (TRG), early recurrence, and short-term survival.
From baseline to approximately 2 months after completion of adjuvant therapy (up to approximately 9 months)
Validation of a pathomic biomarker related to angiogenesis and immune response
Time Frame: At baseline (endoscopic biopsy) and at surgical resection (approximately 3-4 months after treatment initiation)
Validation of a previously developed pathomic biomarker derived from whole-slide HE digital histology, related to vascular architecture and immune cell spatial distribution, as a predictor of response to perioperative FLOT plus durvalumab in gastric and GEJ adenocarcinoma.
At baseline (endoscopic biopsy) and at surgical resection (approximately 3-4 months after treatment initiation)
Characterization of immune evasion mechanisms in non-responders
Time Frame: At surgical resection (approx. 3-4 months after treatment initiation) and approx. 2 months after completion of adjuvant therapy
Characterization of immune evasion mechanisms in the tumor microenvironment of non-responders (TRG 3-4) based on single-cell analyses (scRNA-seq, TCR/BCR-seq) of TILs and PBMCs, including identification of exhausted T cell populations, immunosuppressive cell subsets, and altered antigen presentation pathways.
At surgical resection (approx. 3-4 months after treatment initiation) and approx. 2 months after completion of adjuvant therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis

Collaborators

University of Genova
Humanitas Research Hospital IRCCS, Rozzano-Milan

Investigators

  • Principal Investigator: Carlo Castori, MD, UOC Chirurgia Esofago Gastrica - Istituto "Humanitas" di Milano

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2026

Primary Completion (Estimated)

September 1, 2027

Study Completion (Estimated)

September 1, 2028

Study Registration Dates

First Submitted

July 2, 2026

First Submitted That Met QC Criteria

July 2, 2026

First Posted (Actual)

July 9, 2026

Study Record Updates

Last Update Posted (Actual)

July 9, 2026

Last Update Submitted That Met QC Criteria

July 2, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • GASTRO-IMMUNE-FLOT-2026

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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