Ignite Creation Date:
2024-05-06 @ 1:27 PM
Last Modification Date:
2024-10-26 @ 1:15 PM
Study NCT ID:
NCT04037462
Status:
TERMINATED
Last Update Posted:
2024-06-14
First Post:
2019-07-26
Brief Title:
Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy
Sponsor:
VA Office of Research and Development
Organization:
VA Office of Research and Development
Study Overview
Official Title:
Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy
Status:
TERMINATED
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Low accrual
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Lung cancer accounts for 30 of all cancers among American war Veterans and remains the leading cause of cancer related deaths Half of all lung cancers are metastatic non-small cell lung cancer NSCLC with a 2-year survival rate of 10 Immunotherapy with immune checkpoint inhibitors ICI has emerged as a promising therapeutic strategy that aims to harness the immune system to fight lung cancer However given the modest response rates of 20-25 to these immune checkpoint inhibitors there is a greater desire to extend their benefits to more patients Along with the desire to extend their benefits there is a critical need for the development of novel approaches that can expand the benefit from immune checkpoint inhibitors and create more durable responses prolonging survival from lung cancer The investigators studies show that extended dexamethasone Dex treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor GR overexpressing lung adenocarcinoma AC cell populations Further following withdrawal of Dexamethasone proteins associated with the senescence associated secretory phenotype SASP strongly attracted and expanded T-cells NK cells and monocytes stimulated tumor cell cytolytic activity of NK cells Therefore dexamethasone may induce a persistent senescence phenotype in tumor cell sub-populations expressing moderatehigh levels of GR and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to immune checkpoint inhibitors following complete Dexamethasone withdrawal
Detailed Description:
Lung cancer accounts for 30 of all cancers among American war Veterans and remains the leading cause of cancer related deaths Half of all lung cancers are metastatic non-small cell lung cancer NSCLC with a 2-year survival rate of 10 Immunotherapy with immune checkpoint inhibitors ICI has emerged as a promising therapeutic strategy that aims to harness the immune system to fight lung cancer However given the modest response rates of 20-25 to these immune checkpoint inhibitors there is a greater desire to extend their benefits to more patients Along with the desire to extend their benefits there is a critical need for the development of novel approaches that can expand the benefit from immune checkpoint inhibitors and create more durable responses prolonging survival from lung cancer
Our studies show that extended dexamethasone Dex treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor GR overexpressing lung adenocarcinoma AC cell populations Further following withdrawal of Dexamethasone proteins associated with the senescence associated secretory phenotype SASP particularly CCL2 CCL4 CXCL1 and CXCL2 strongly attracted and expanded T-cells NK cells and monocytes stimulated tumor cell cytolytic activity of NK cells
Our overarching hypothesis is that in lung adenocarcinoma patients who are not on baseline steroids pre-treatment with Dexamethasone will induce a persistent senescence phenotype in tumor cell sub-populations expressing moderatehigh levels of GR and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to immune checkpoint inhibitors following complete Dexamethasone withdrawal The investigators will test this hypothesis through the conduct of the following aims
Specific Aim 1 Use FLT-PET imaging and blood analysis to test whether a 7-14-day pre-treatment of lung adenocarcinoma patients with Dexamethasone followed by Dexamethasone withdrawal will induce persistent senescence related cell cycle arrest in 1 lesion in 60 of patients based on GR expression accompanied by release of SASP proteins and activation of T and NK cells
Specific Aim 2 Test whether a 7-14-day pre-treatment of lung adenocarcinoma patients with Dexamethasone followed by Dexamethasone withdrawal and subsequent re-challenge with pembrolizumab will yield an overall response rate ORR of 33 to pembrolizumab in association with tumor GR status SASP and immune cell activation
These aims will be conducted through a Phase II clinical trial designed as a single-arm two-stage study in Veterans whose lung adenocarcinoma has progressed on immune checkpoint inhibitors Based on the investigators preliminary data the investigators expect that Dexamethasone will induce tumor senescence in at least one lesion in 60 of patients and secondarily improve overall response to pembrolizumab by 33 Success with these aims would inform a larger study that could potentially change the way the investigators approach patients with primary or acquired resistance to immune checkpoint inhibitors with an off the shelf medication that could re-sensitize lung adenocarcinoma to immune checkpoint inhibitors The proposed research could substantially benefit Veterans with metastatic NSCLC a group with the most genomically complex lung cancers and poor survival
Our studies show that extended dexamethasone Dex treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor GR overexpressing lung adenocarcinoma AC cell populations Further following withdrawal of Dexamethasone proteins associated with the senescence associated secretory phenotype SASP particularly CCL2 CCL4 CXCL1 and CXCL2 strongly attracted and expanded T-cells NK cells and monocytes stimulated tumor cell cytolytic activity of NK cells
Our overarching hypothesis is that in lung adenocarcinoma patients who are not on baseline steroids pre-treatment with Dexamethasone will induce a persistent senescence phenotype in tumor cell sub-populations expressing moderatehigh levels of GR and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to immune checkpoint inhibitors following complete Dexamethasone withdrawal The investigators will test this hypothesis through the conduct of the following aims
Specific Aim 1 Use FLT-PET imaging and blood analysis to test whether a 7-14-day pre-treatment of lung adenocarcinoma patients with Dexamethasone followed by Dexamethasone withdrawal will induce persistent senescence related cell cycle arrest in 1 lesion in 60 of patients based on GR expression accompanied by release of SASP proteins and activation of T and NK cells
Specific Aim 2 Test whether a 7-14-day pre-treatment of lung adenocarcinoma patients with Dexamethasone followed by Dexamethasone withdrawal and subsequent re-challenge with pembrolizumab will yield an overall response rate ORR of 33 to pembrolizumab in association with tumor GR status SASP and immune cell activation
These aims will be conducted through a Phase II clinical trial designed as a single-arm two-stage study in Veterans whose lung adenocarcinoma has progressed on immune checkpoint inhibitors Based on the investigators preliminary data the investigators expect that Dexamethasone will induce tumor senescence in at least one lesion in 60 of patients and secondarily improve overall response to pembrolizumab by 33 Success with these aims would inform a larger study that could potentially change the way the investigators approach patients with primary or acquired resistance to immune checkpoint inhibitors with an off the shelf medication that could re-sensitize lung adenocarcinoma to immune checkpoint inhibitors The proposed research could substantially benefit Veterans with metastatic NSCLC a group with the most genomically complex lung cancers and poor survival
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None