A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors
| Autor: | Tomislav Dragovich, H. Calvert, M. Squires, C. Pretzinger, D. M. Rensvold, Sandy Kurtin, Daruka Mahadevan, Victoria Lock, Ruth Plummer, Donna M. Smith, D. D. Von Hoff, J. Adams |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Antineoplastic Agents Pharmacology QT interval Drug Administration Schedule Piperidines Pharmacokinetics Refractory Cyclin-dependent kinase Neoplasms Mucositis medicine Humans Infusions Intravenous Protein Kinase Inhibitors Aged Aged 80 and over Dose-Response Relationship Drug biology business.industry Hematology Middle Aged medicine.disease Cyclin-Dependent Kinases Dose–response relationship Oncology Tolerability Pharmacodynamics biology.protein Pyrazoles Female business |
| Zdroj: | Annals of Oncology. 22:2137-2143 |
| ISSN: | 0923-7534 |
| DOI: | 10.1093/annonc/mdq734 |
| Popis: | 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/m2/day). At 40 mg/m2/day, one patient developed hypotension and ST segment elevation. At 34 mg/m2/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/m2. Conclusion AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation. |
| Databáze: | OpenAIRE |
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