BACKGROUND: AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). PATIENTS AND METHODS: AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained. RESULTS: Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2). CONCLUSION: AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.
BACKGROUND: AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). PATIENTS AND METHODS: AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained. RESULTS: Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2). CONCLUSION: AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.
Authors: Ana L Alessandri; Rodger Duffin; Andrew E Leitch; Christopher D Lucas; Tara A Sheldrake; David A Dorward; Nik Hirani; Vanessa Pinho; Lirlândia Pires de Sousa; Mauro M Teixeira; John F Lyons; Christopher Haslett; Adriano G Rossi Journal: PLoS One Date: 2011-09-30 Impact factor: 3.240
Authors: M Emmy M Dolman; Evon Poon; Marli E Ebus; Ilona J M den Hartog; Carel J M van Noesel; Yann Jamin; Albert Hallsworth; Simon P Robinson; Kevin Petrie; Rolf W Sparidans; Robbert J Kok; Rogier Versteeg; Huib N Caron; Louis Chesler; Jan J Molenaar Journal: Clin Cancer Res Date: 2015-07-22 Impact factor: 12.531
Authors: Aslamuzzaman Kazi; Liwei Chen; Shengyan Xiang; Rajanikanth Vangipurapu; Hua Yang; Francisca Beato; Bin Fang; Terence M Williams; Kazim Husain; Patrick Underwood; Jason B Fleming; Mokenge Malafa; Eric A Welsh; John Koomen; José Trevino; Saïd M Sebti Journal: Clin Cancer Res Date: 2021-04-20 Impact factor: 12.531