NCT02593019

Phase II, Single-arm Study of AZD1775 Monotherapy in Relapsed Small Cell Lung Cancer Patients

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 24 (actual)
• Sponsor: Samsung Medical Center · Academic / Other
• Sex: All
• Age: 20 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Small Cell Lung Cancer

Interventions

Type	Name	Description
DRUG	AZD1775	AZD1775 175 mg BID per os every 12 hours (6 doses) administered days 1-3 the first week and then days 1-3 the 2nd week of 21 day cycle. Tumour evaluation using RECIST 1.1 will be conducted at screening (within 28 days prior to first dose) and every 6 weeks relative to the date of first dose, up to week 42, then every 9 weeks until objective disease progression (within a window of +/- 7 days of the scheduled date).

Timeline

• Start date: 2015-12-01
• Primary completion: 2018-10-01
• Completion: 2018-10-01
• First posted: 2015-10-30
• Last updated: 2021-03-19

Locations

1 site across 1 country: South Korea