Phase II, Single-arm Study of AZD1775 Monotherapy in Relapsed Small Cell Lung Cancer Patients
Status:
Completed
Trial end date:
2018-10-01
Target enrollment:
Participant gender:
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.