Gastric Cancer Clinical Trial
Official title:
Prospective Validation of a DNA Damage Repair-Hippo Pathway Signature in Patients With Advanced Gastric Cancer
Verified date | January 2024 |
Source | Regina Elena Cancer Institute |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Observational |
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.
Status | Active, not recruiting |
Enrollment | 167 |
Est. completion date | August 30, 2024 |
Est. primary completion date | August 30, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: - 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. Exclusion Criteria: - Previous chemotherapy for metastatic disease; - Comorbidities not controlled with appropriate medical therapy; - Brain metastasis; - Patient unable to give adequate consent for the study |
Country | Name | City | State |
---|---|---|---|
Italy | "Regina Elena" National Cancer Institute | Rome |
Lead Sponsor | Collaborator |
---|---|
Regina Elena Cancer Institute | Azienda Ospedaliera "Sant'Andrea", Azienda Ospedaliero Universitaria Policlinico Modena, Azienda Sanitaria Locale n. 2 - Lanciano Vasto Chieti, Campus Bio-Medico University, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, University of Roma La Sapienza |
Italy,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | |
Primary | 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 |
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