Prospective Validation of a DNA Damage Repair-Hippo Pathway Signature in Patients With Advanced Gastric Cancer

NCT06204523 | Unknown DMC

• 1 other identifier: RS1043/18
• Study Type: observational
• Target: 167
• Locations: 1 country
• Sites: 1

Brief Summary

We envisioned a scenario where the interaction between the ATM-Chk2/ATR-Chk1 pathways and Hippo enables GC cells to overcome chemotherapy-induced death stimuli. First, ATM-Chk2 and ATR-Chk1 were found to be activated across all the GC molecular subtypes. Moreover, a number of genes associated with their basal activation are recurrently mutated or amplified. Thus, we retrospectively characterized a cohort of GC patients treated with first-line therapy for DDR- and Hippo-related markers, identifying a signature predicting inferior PFS and OS. This exploratory analysis provided the necessary information (frequency of candidate biomarkers and effect difference between groups) for a prospective study with validation purposes, which is the main goal of this trial.

Conditions

DNA Damage; Gastric Cancer

Outcome Measures

Primary Outcomes (3)

• Identify new biomarkers that predict the activity of first-line chemotherapy, in order to achieve better patient selection.

  Computational enrichment analysis will be carried out to test whether tumors of patients with shorter PFS contain a higher-than-randomly-expected representation of a specific pathway/function. Special emphasis will be placed on, but not limited to, the DDR-Hippo-Wnt pathways. For multiple hypothesis testing a Benjamini-Hochberg False Discovery Rate correction will be applied (\<5%). For clinical data analysis, the Pearson's Chi-squared test of independence (2-tailed) and the Pearson's correlation coefficient will be used to assess the relationships between categorical and continuous variables, respectively.

  Three years

• Identify additional genetic events molecularly linked to the DDR-Hippo signature and potentially improve its predictive ability.

  RNA and DNA will be extracted from 5µm FFPE tissue sections using the AllPrep DNA/RNA FFPE kit (Qiagen). Libraries for RNA-Seq will be prepared using the TruSeq Stranded Total RNA kit with an initial ribosomal depletion step (Illumina). Targeted DNA-Sequencing will be conducted by designing a custom amplicon panel with DesignStudio and employing the TruSeq Custom Amplicon Low Input Kit (Illumina). RNA will be analyzed with our cloud pipeline (RAP, available at https://bioinformatics.cineca.it/rap/) that employs the Tuxedo Suite (Tophat, Cufflinks, Cuffdiff). For DNA analysis, applications available on Basespace (Illumina) will be used. Sequencing will be performed on our NextSeq500

  Three years

• Investigate pathways of interest at a deeper level, as well as identify other potential pathways/functions impacting clinical outcomes.

  Clinical, pathological and molecular variables will be tested in univariate Cox analysis. A multivariate Cox proportional hazard model for PFS will be build with variables testing significant at the univariate assessment, and the related estimates reported as HR and 95%CI.

  Three years

Study Arms (1)

Popolation

Diagnostic Test: investigated biomarkers regarding the efficacy of first-line chemotherapy

Interventions

investigated biomarkers regarding the efficacy of first-line chemotherapy DIAGNOSTIC_TEST

The present study was designed to generate solid evidence on the predictivity of the investigated biomarkers regarding the efficacy of first-line chemotherapy in patients with GC

Popolation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with inoperable locally advanced or metastatic GC who are candidates for first-line chemotherapy treatment and meet the following criteria will be included in the study

You may qualify if:

• Age \>18 years;
• Histologic diagnosis of locally advanced or metastatic gastric carcinoma (GC) or gastroesophageal junction carcinoma (EJC);
• Biological material adequate for molecular analysis to be performed, taken (at surgery or by biopsy) prior to the administration of any anti-tumor treatment (chemotherapy and/or radiotherapy);
• ECOG PS 0-2;
• Adequate hematologic, hepatic, and renal function;
• Measurable disease according to RECIST criteria;
• Written informed consent.

You may not qualify if:

• Previous chemotherapy for metastatic disease;
• Comorbidities not controlled with appropriate medical therapy;
• Brain metastasis;
• Patient unable to give adequate consent for the study

Sponsors & Collaborators

• Regina Elena Cancer Institute: lead
• Azienda Sanitaria Locale n. 2 - Lanciano Vasto Chieti: collaborator
• Campus Bio-Medico University: collaborator
• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: collaborator
• Azienda Ospedaliera "Sant'Andrea": collaborator
• University of Roma La Sapienza: collaborator
• Azienda Ospedaliero Universitaria Policlinico Modena: collaborator

Study Sites (1)

"Regina Elena" National Cancer Institute

Rome, 00144, Italy

Location

MeSH Terms

Conditions

Stomach Neoplasms

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 28, 2023
• First Posted: January 12, 2024
• Study Start: October 26, 2018
• Primary Completion: August 30, 2023
• Study Completion: August 30, 2024
• Last Updated: January 18, 2024

Record last verified: 2024-01

Locations

IT (1)