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

2 juli 2026 bijgewerkt door: 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.

Studie Overzicht

Toestand

Nog niet aan het werven

Conditie

Gedetailleerde beschrijving

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.

Studietype

Observationeel

Inschrijving (Geschat)

250

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Contact Back-up

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

  • Volwassen
  • Oudere volwassene

Accepteert gezonde vrijwilligers

Nee

Bemonsteringsmethode

Niet-waarschijnlijkheidssteekproef

Studie Bevolking

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.

Beschrijving

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Cohorten en interventies

Groep / 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.

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Identification of immune and angiogenic cellular subsets associated with pathological response to perioperative FLOT plus durvalumab
Tijdsspanne: 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

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Association between angiogenic and immune signatures and clinical outcomes
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis

Medewerkers

University of Genova
Humanitas Research Hospital IRCCS, Rozzano-Milan

Onderzoekers

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

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Geschat)

1 september 2026

Primaire voltooiing (Geschat)

1 september 2027

Studie voltooiing (Geschat)

1 september 2028

Studieregistratiedata

Eerst ingediend

2 juli 2026

Eerst ingediend dat voldeed aan de QC-criteria

2 juli 2026

Eerst geplaatst (Werkelijk)

9 juli 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

9 juli 2026

Laatste update ingediend die voldeed aan QC-criteria

2 juli 2026

Laatst geverifieerd

1 juli 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Andere studie-ID-nummers

  • GASTRO-IMMUNE-FLOT-2026

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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