Ignite Creation Date:
2024-05-06 @ 7:45 AM
Last Modification Date:
2024-10-26 @ 11:52 AM
Study NCT ID:
NCT02593019
Status:
COMPLETED
Last Update Posted:
2021-03-19
First Post:
2015-10-28
Brief Title:
Phase II Single-arm Study of AZD1775 Monotherapy in Relapsed Small Cell Lung Cancer Patients
Sponsor:
Samsung Medical Center
Organization:
Samsung Medical Center
Study Overview
Official Title:
Phase II Single-arm Study of AZD1775 Monotherapy in Relapsed Small Cell Lung Cancer Patients
Status:
COMPLETED
Status Verified Date:
2021-03
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:
None
Brief Summary:
AZD1775 previously known as MK-1775 in earlier studies is an inhibitor of Wee1 a protein tyrosine kinase Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 CDK1 and 2 CDK2 and is involved in regulation of the intra-S and G2 cell cycle checkpoints
CDK1 also called cell division cycle 2 or CDC2 activity drives a cell from the G2 phase of the cell cycle into mitosis In response to DNA damage Wee1 inhibits CDK1 to prevent the cell from dividing until the damaged DNA is repaired G2 checkpoint arrest
Inhibition of Wee1 is expected to release a tumor cell from chemotherapeutically-induced arrest of cell replication In vitro experiments demonstrate that AZD1775 has synergistic cytotoxic effects when administered in combination with various DNA damaging agents that have divergent mechanisms of action Therefore the primary objective of the clinical development of AZD1775 is its use as a chemosensitizing drug in combination with a cytotoxic agent or combination of agents for treatment of advanced solid tumors
CDK2 activity drives a cell into and through S-phase of the cell cycle where the genome is duplicated in preparation for cell division Inhibition of Wee1 is expected to cause aberrantly high CDK2 activity in S-phase cells which in turn leads to unstable DNA replication structures and ultimately DNA damage Therefore it is anticipated that AZD1775 will have independent anti-tumor activity in the absence of added chemotherapy
The tumor suppressor protein p53 regulates the G1 checkpoint As the majority of human cancers harbor abnormalities in this pathway they become more dependent on S- and G2- phase checkpoints Thus S- and G2-checkpoint abrogation caused by inhibition of Wee1 may selectively sensitize p53-deficient cells
One hundred percent of Small cell lung cancer has TP53 mutation therefore we can expect that most of Small cell lung cancer have lost G1 checkpoint and has high probability of WEE1 dependency for proper DNA repair and cell cycle progression For this reason Small cell lung cancer could be a good clinical trial target disease for WEE1 inhibitor
CDK1 also called cell division cycle 2 or CDC2 activity drives a cell from the G2 phase of the cell cycle into mitosis In response to DNA damage Wee1 inhibits CDK1 to prevent the cell from dividing until the damaged DNA is repaired G2 checkpoint arrest
Inhibition of Wee1 is expected to release a tumor cell from chemotherapeutically-induced arrest of cell replication In vitro experiments demonstrate that AZD1775 has synergistic cytotoxic effects when administered in combination with various DNA damaging agents that have divergent mechanisms of action Therefore the primary objective of the clinical development of AZD1775 is its use as a chemosensitizing drug in combination with a cytotoxic agent or combination of agents for treatment of advanced solid tumors
CDK2 activity drives a cell into and through S-phase of the cell cycle where the genome is duplicated in preparation for cell division Inhibition of Wee1 is expected to cause aberrantly high CDK2 activity in S-phase cells which in turn leads to unstable DNA replication structures and ultimately DNA damage Therefore it is anticipated that AZD1775 will have independent anti-tumor activity in the absence of added chemotherapy
The tumor suppressor protein p53 regulates the G1 checkpoint As the majority of human cancers harbor abnormalities in this pathway they become more dependent on S- and G2- phase checkpoints Thus S- and G2-checkpoint abrogation caused by inhibition of Wee1 may selectively sensitize p53-deficient cells
One hundred percent of Small cell lung cancer has TP53 mutation therefore we can expect that most of Small cell lung cancer have lost G1 checkpoint and has high probability of WEE1 dependency for proper DNA repair and cell cycle progression For this reason Small cell lung cancer could be a good clinical trial target disease for WEE1 inhibitor
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None