Ignite Creation Date:
2024-05-06 @ 8:18 PM
Last Modification Date:
2024-10-26 @ 3:24 PM
Study NCT ID:
NCT06321640
Status:
RECRUITING
Last Update Posted:
2024-03-20
First Post:
2024-03-13
Brief Title:
Study for the Multidimensional Analyses of Resistance and Toxicity to Immune- and Targeted-therapies
Sponsor:
European Institute of Oncology
Organization:
European Institute of Oncology
Study Overview
Official Title:
POSITive Prospective Observational Study for the Multidimensional Analyses of Resistance and Toxicity to Immune- and Targeted-therapies
Status:
RECRUITING
Status Verified Date:
2024-03
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:
POSITive
Brief Summary:
Novel treatment modalities like targeted therapies and Immune checkpoint inhibitors have revolutionised the therapeutic landscape in oncology and hematology significantly improving outcomes even in clinical contexts in which little improvement had been observed for decades such as metastatic melanoma lung cancer and lymphoproliferative neoplasms such as chronic lymphoid leukemia or Hodgkin lymphoma However major issues remain unsolved given the frequent occurrence of primary or secondary resistance and the still incomplete understanding of the physiopathology of adverse events which represent a major cause of morbidity and treatment interruption and often remain difficult to treat and diagnose In this complex landscape identifying the best treatment option for each patient remains challenging For both targeted therapies and Immune checkpoint inhibitors several biomarkers have been reported but their implementation in clinical practice is still uncommon and most of the decision-making process remains based on purely clinical considerations or constraints dictated by the regulatory bodies Obstacles to biomarker-driven decision making are manifold and include insufficient understanding of the underlying biology lack of strong evidence on their predictive power and limited tumor sampling which may be circumvented by non-invasive techniques such as liquid biopsies
Detailed Description:
Biomarkers to predict response and toxicity to Targeted Therapies Targeted therapies such as kinase inhibitors are usually associated with extremely elevated response rates precisely because their use requires the prior detection of a companion biomarker However secondary resistance almost invariably develops resulting in often moderate improvements in overall survival despite major delays in disease progression Resistance mechanisms can be broadly classified in two groups i cis-mutations that directly impinge on the binding of the drug to its target and ii trans alterations that activate additional pathways able to override drug-induced inhibition or transcriptional upregulation of parallel pathways In both cases these mutations are mostly acquired as an evolutionary response to the selective environment generated by the drug itself and their identification is crucial to identify potential subsequent treatments able to circumvent the resistance mechanism As more targeted therapies enter clinical practice including novel classes like Antibody-drug conjugates which maintain high target specificity but have completely different mechanisms of action extensive investigation of the molecular mechanisms associated with secondary resistance becomes more and more relevant
Furthermore many targeted therapies are associated with specific toxicities such as interstitial lung disease that are themselves poorly characterized from a mechanistic point of view and this lack of knowledge prevents effective diagnosis and treatment
Biomarkers to predict response and toxicity to Immune Checkpoint Inhibitors Several biomarkers with predictive power in Immune checkpoint inhibitorsI-treated patients have been reported eg tumor mutational burden extent of tumour T-cell infiltration at baseline expression by tumor cells of the respective Immune checkpoint inhibitors targets However each of these individually bears very little accuracy for outcome A recent meta-analysis of tumor-intrinsic data across 1000 patients and multiple tumor types elaborated a multivariable predictive model for each cancer type using 11 features derived from genomic whole exome sequencing and transcriptomic total ribonucleic acid sequencing data of primary tumors see below for the list of markers The multivariable predictor attained an Afea Under the Receiver-Operating Characteristic value of 086 thus strongly indicating that an integrated assessment of multiple and novel biomarkers achieves an accuracy that can significantly impact on decision making Moreover recent findings suggest a critical role for the gut microbiome Notably specific species in the gut microbiota promote anti-cancer immunity during Immune checkpoint inhibitors treatment which can be transferred by faecal microbiome transplantation to rescues Immune checkpoint inhibitors sensitivity in model systems Underlying molecular mechanisms however are unknown and may involve immunological mimicry of tumour neoantigens by microbial peptides from the gut or tumor microbiota
The issue of drug-related toxicities Immune-related Adverse events is possibly even more crucial in Immune checkpoint inhibitors-treated patients Immune-related Adverse events commonly develop after a long latency are associated with significant morbidity and mortality and often represent a reason for treatment discontinuation and disease relapse Immune-related Adverse events are often difficult to diagnose since their pathophysiology is different from that of clinically similar idiopathic autoimmune disorders Despite the definition of consensus guidelines on the diagnosis and treatment of Immune-related Adverse events therapeutic options are limited and invariably include generalized immune suppression to the detriment of the anticancer response Biomarkers strongly predictive or diagnostic of Immune-related Adverse events have not been identified to date Some studies have identified specific cytokine combinations but these studies remain correlative and require validation in larger cohorts and different clinical contexts
Furthermore many targeted therapies are associated with specific toxicities such as interstitial lung disease that are themselves poorly characterized from a mechanistic point of view and this lack of knowledge prevents effective diagnosis and treatment
Biomarkers to predict response and toxicity to Immune Checkpoint Inhibitors Several biomarkers with predictive power in Immune checkpoint inhibitorsI-treated patients have been reported eg tumor mutational burden extent of tumour T-cell infiltration at baseline expression by tumor cells of the respective Immune checkpoint inhibitors targets However each of these individually bears very little accuracy for outcome A recent meta-analysis of tumor-intrinsic data across 1000 patients and multiple tumor types elaborated a multivariable predictive model for each cancer type using 11 features derived from genomic whole exome sequencing and transcriptomic total ribonucleic acid sequencing data of primary tumors see below for the list of markers The multivariable predictor attained an Afea Under the Receiver-Operating Characteristic value of 086 thus strongly indicating that an integrated assessment of multiple and novel biomarkers achieves an accuracy that can significantly impact on decision making Moreover recent findings suggest a critical role for the gut microbiome Notably specific species in the gut microbiota promote anti-cancer immunity during Immune checkpoint inhibitors treatment which can be transferred by faecal microbiome transplantation to rescues Immune checkpoint inhibitors sensitivity in model systems Underlying molecular mechanisms however are unknown and may involve immunological mimicry of tumour neoantigens by microbial peptides from the gut or tumor microbiota
The issue of drug-related toxicities Immune-related Adverse events is possibly even more crucial in Immune checkpoint inhibitors-treated patients Immune-related Adverse events commonly develop after a long latency are associated with significant morbidity and mortality and often represent a reason for treatment discontinuation and disease relapse Immune-related Adverse events are often difficult to diagnose since their pathophysiology is different from that of clinically similar idiopathic autoimmune disorders Despite the definition of consensus guidelines on the diagnosis and treatment of Immune-related Adverse events therapeutic options are limited and invariably include generalized immune suppression to the detriment of the anticancer response Biomarkers strongly predictive or diagnostic of Immune-related Adverse events have not been identified to date Some studies have identified specific cytokine combinations but these studies remain correlative and require validation in larger cohorts and different clinical contexts
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