Ignite Creation Date:
2024-05-06 @ 7:59 PM
Last Modification Date:
2024-10-26 @ 3:17 PM
Study NCT ID:
NCT06204523
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-01-18
First Post:
2023-03-28
Brief Title:
Prospective Validation of a DNA Damage Repair-Hippo Pathway Signature in Patients With Advanced Gastric Cancer
Sponsor:
Regina Elena Cancer Institute
Organization:
Regina Elena Cancer Institute
Study Overview
Official Title:
Prospective Validation of a DNA Damage Repair-Hippo Pathway Signature in Patients With Advanced Gastric Cancer
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
We envisioned a scenario where the interaction between the ATM-Chk2ATR-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
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
Detailed Description:
This prospective multicenter non-interventional trial is designed for prospectively validating the DDR-Hippo signature as a predictor of inferior PFS in patients with inoperable locally advanced or metastatic GC receiving first-line therapy Patients will be evaluated for response to chemotherapy every two cycles by current RECIST criteria PFS will be defined as the time elapsing between the initiation of chemotherapy until objective tumor progression or death and OS as the time elapsing between the initiation of chemotherapy until death from any cause All molecular analyses will be centralized at the coordinating center Investigators performing molecular analyses will be masked to clinical outcomes Centralized radiological review is planned The study will be conducted in accordance with the Declaration of Helsinki and adheres to the REMARK criteria
The second task is designed for exploring genetic events functionally related to the DDR and Hippo pathways that may modify the predictive significance of the signature These genes are schematically clustered on the basis of the expected alteration in i Mutated genes cluster 1 to be evaluated by targeted DNA-Seq and amplified genes cluster 2 to be evaluated by FISHCISH Cluster 1 includes TP53 defective cell cycle progression and apoptotic response aberrant TAZYAP-mediated transcription KRAS oncogene-induced replication stress and activation of cell cycle checkpoints to avoid apoptosis and senescence BRCA1 and BRCA2 defective homologous recombination repair ARID1A ATR and ATM altered ATMATR-initiated DNA repair RHOA G-protein coupled receptor-mediated activation of TAZYAP CTNNB1 APC and FBXW7 Wnt-mediated control of TAZYAP Cluster 2 encompasses MYC and KRAS oncogene-induced replication stress CCNE1 CCND1 and CDK6 dysfunctional G1-S transition requiring compensatory activation of intra-S and G2M checkpoints
The present study is designed to generate prospective evidence on the ability of the investigated biomarkers to predict the efficacy of first-line chemotherapy in GC patients The identification of patients who derive marginal benefit from chemotherapy holds the potential to expedite a wave of interventional trials with agents targeting the DDR-Hippo network eg PARP inhibitors and ATR-Chk1 and ATM-Chk2 inhibitors as well as to delineate the target population for studies with other compounds such as immune checkpoint inhibitors Overall the experimental approach we propose is expected to culminate in the generation of a new tool to be used on a routine basis
The second task is designed for exploring genetic events functionally related to the DDR and Hippo pathways that may modify the predictive significance of the signature These genes are schematically clustered on the basis of the expected alteration in i Mutated genes cluster 1 to be evaluated by targeted DNA-Seq and amplified genes cluster 2 to be evaluated by FISHCISH Cluster 1 includes TP53 defective cell cycle progression and apoptotic response aberrant TAZYAP-mediated transcription KRAS oncogene-induced replication stress and activation of cell cycle checkpoints to avoid apoptosis and senescence BRCA1 and BRCA2 defective homologous recombination repair ARID1A ATR and ATM altered ATMATR-initiated DNA repair RHOA G-protein coupled receptor-mediated activation of TAZYAP CTNNB1 APC and FBXW7 Wnt-mediated control of TAZYAP Cluster 2 encompasses MYC and KRAS oncogene-induced replication stress CCNE1 CCND1 and CDK6 dysfunctional G1-S transition requiring compensatory activation of intra-S and G2M checkpoints
The present study is designed to generate prospective evidence on the ability of the investigated biomarkers to predict the efficacy of first-line chemotherapy in GC patients The identification of patients who derive marginal benefit from chemotherapy holds the potential to expedite a wave of interventional trials with agents targeting the DDR-Hippo network eg PARP inhibitors and ATR-Chk1 and ATM-Chk2 inhibitors as well as to delineate the target population for studies with other compounds such as immune checkpoint inhibitors Overall the experimental approach we propose is expected to culminate in the generation of a new tool to be used on a routine basis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None