Ignite Creation Date:
2024-05-06 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 12:50 PM
Study NCT ID:
NCT03614013
Status:
UNKNOWN
Last Update Posted:
2018-08-06
First Post:
2018-07-30
Brief Title:
Resistance to Immunotherapy in Gastric Cancer
Sponsor:
Pontificia Universidad Catolica de Chile
Organization:
Pontificia Universidad Catolica de Chile
Study Overview
Official Title:
Mechanisms of Resistance to Immunotherapy Based on Checkpoint Inhibitors in Metastatic Gastric Cancers
Status:
UNKNOWN
Status Verified Date:
2018-08
Last Known Status:
ACTIVE_NOT_RECRUITING
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:
MERIT
Brief Summary:
This project seeks to analyze and define the mechanism s involved in the resistance to checkpoint therapy in metastatic GC patients The investigators propose the use of a Next-Generation Sequencing NGS assay that involves 395 genes allowing us to define a specific molecular signature to characterize responder and non-responder patients to checkpoint therapy in combination with IHC analyses of specific factors Such signature s could then be used to predict which individuals who might get the most benefit out of checkpoint therapy treatment Analysis will be perfomed retrospectively using biopsies provided by mGC patients recruited at the Red de Salud UC treated with checkpoint therapy the response of patients to treatment is evaluated by RECIST 11 criteria and thereby they are classified as responders or non-responders
Detailed Description:
In Chile gastric cancer GC is the leading cause of cancer death killing 178 in 100000 peopleyear Most GC cases are diagnosed at advance stage indeed 70 of diagnosed patients are stage IV classified as metastatic GC mGC Median survival rates with standard chemotherapy is 6 months In recent years the development of immune checkpoint inhibitors that activate a sustained T-cell response has revolutionized oncology treatments Indeed humanized monoclonal antibodies against the CTLA4 and PD1PDL1 pathways treatments a strategy commonly called checkpoint therapy has demonstrated effective against many malignancies Despite this a substantial percentage of patients 60 remain unresponsive or display non-significant clinical responses to these regimes Previous studies suggest that cancer cells employ a variety of strategies to become resistant to these therapies these can include existence of genomic alterations in their mutational landscape that cause immune suppression inhibition of the Interferon IFN gamma pathway among others upregulation of alternative immune checkpoints other than CTLA4 or PD1PDL1 and upregulation of the Indoleamine 23-DyOxygenase IDO enzyme
HYPOTHESIS
Metastatic GC patients whose tumor microenvironment presents a specific mutational landscape increased levels of alternative immune co-inhibitors and enhanced IDO expression fail determined by RECIST 11 in response to checkpoint therapy
In order to validate this hypothesis the investigators will
1 Retrospectively collect samples derived from mGC patients who received checkpoint therapy and clinical data including RECIST 11 Response Evaluation Criteria In Solid Tumors to classify them as responders or non-responders to checkpoint therapy
2 Obtain RNADNA samples from stored patient biopsies in order to perform a comprehensive analysis of mutational landscape using Next Generation Sequencing NGS methods
3 Analyze tissue samples from patients by immunohistochemistry to evaluate expression of the IDO enzyme and the levels of alternative immune co-inhibitors
Therefore this proposal will use samples derived from mGC patients who received checkpoint therapy at the Cancer center of the Clinical Hospital at the Pontificia Universidad Catolica de Chile Biopsies paraffin embedded samples and full clinical history are available for analysis The team of investigators is composed by both physicians MD and molecular biologists PhD Dr Garrido and clinical coordinator Dr Retamal will select patients obtain cancer samples and perform correlations with treatment outcome and coordinate the immunohistochemistry The laboratory of Dr Owen co-investigator in this proposal with Dr Pinto has vast experience in the field of molecular oncology and will perform the molecular analysis
The overall goal of this proposal is to elucidate the molecular mechanisms involved in the resistance to CTLA4PD1PDL1 targeted checkpoint therapy in mGC patients The relevance lies in the high prevalence and mortality rates of this disease in Chile Finally its significance stems from the potential discovery and characterization diagnostic companion biomarkers that could allow stratification in order to identify mGC patients that could get the most benefit from checkpoint therapy regimes
HYPOTHESIS
Metastatic GC patients whose tumor microenvironment presents a specific mutational landscape increased levels of alternative immune co-inhibitors and enhanced IDO expression fail determined by RECIST 11 in response to checkpoint therapy
In order to validate this hypothesis the investigators will
1 Retrospectively collect samples derived from mGC patients who received checkpoint therapy and clinical data including RECIST 11 Response Evaluation Criteria In Solid Tumors to classify them as responders or non-responders to checkpoint therapy
2 Obtain RNADNA samples from stored patient biopsies in order to perform a comprehensive analysis of mutational landscape using Next Generation Sequencing NGS methods
3 Analyze tissue samples from patients by immunohistochemistry to evaluate expression of the IDO enzyme and the levels of alternative immune co-inhibitors
Therefore this proposal will use samples derived from mGC patients who received checkpoint therapy at the Cancer center of the Clinical Hospital at the Pontificia Universidad Catolica de Chile Biopsies paraffin embedded samples and full clinical history are available for analysis The team of investigators is composed by both physicians MD and molecular biologists PhD Dr Garrido and clinical coordinator Dr Retamal will select patients obtain cancer samples and perform correlations with treatment outcome and coordinate the immunohistochemistry The laboratory of Dr Owen co-investigator in this proposal with Dr Pinto has vast experience in the field of molecular oncology and will perform the molecular analysis
The overall goal of this proposal is to elucidate the molecular mechanisms involved in the resistance to CTLA4PD1PDL1 targeted checkpoint therapy in mGC patients The relevance lies in the high prevalence and mortality rates of this disease in Chile Finally its significance stems from the potential discovery and characterization diagnostic companion biomarkers that could allow stratification in order to identify mGC patients that could get the most benefit from checkpoint therapy regimes
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