A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors

Abstract

AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.

The CDK inhibitors in cancer research and therapy

“…This compound had lower potency against other CDKs tested (CDK3 and CDK7) and was inactive against all of the non-CDK kinases tested with the exception of GSK3 (IC 50 = 0.089 M). Phase I clinical trial was carried out in 28 patients with refractory solid tumors (Mahadevan et al 2011). Electrocardiogram showed a dose-dependent increase in QTc.…”

Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging

“…Single AT7519 treatment of patients with advanced/metastatic solid tumors or refractory non-Hodgkin's lymphoma will provide data to applicable dose, pharmacokinetics, pharmacodynamics and side effects. First results of this study suggested evidence of clinical activity of AT7519, due to reduction of PCNA, a protein required for DNA replication, as a result of Cdk inhibition and an increase of apoptosis markers (Mahadevan et al, 2011). Mucositis, neutropenia, and reversible thrombocytopenia were identified as dose limiting toxicities.…”

Cytokeratin 18 (CK18) and Caspase-Cleaved CK18 (ccCK18) as Response Markers in Anticancer Therapy

“…Soluble CK18 fragments allowed detection of seliciclibinduced cell death in the blood of patients treated at doses above 800 mg/day. Another CDK inhibitor, namely AT7519, afforded stable disease for >6 months in four out of 28 patients and a prolonged partial response in one patient bearing solid tumors (Mahadevan et al, 2011). Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity.…”