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

• Published in: Annals of oncology Vol. 22; no. 9; pp. 2137 - 2143
• Main Authors: Mahadevan, D., Plummer, R., Squires, M.S., Rensvold, D., Kurtin, S., Pretzinger, C., Dragovich, T., Adams, J., Lock, V., Smith, D.M., Von Hoff, D., Calvert, H.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-09-2011; Oxford University Press
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; AT7519; Biological and medical sciences; cyclin-dependent kinases; Cyclin-Dependent Kinases - antagonists & inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - metabolism; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; Piperidines - administration & dosage; Piperidines - adverse effects; Piperidines - pharmacokinetics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Pyrazoles - administration & dosage; Pyrazoles - adverse effects; Pyrazoles - pharmacokinetics; refractory solid tumors; Tumors; pharmacokinetics; refractory solid tumors; cyclin-dependent kinases; AT7519; pharmacodynamics; Human; Pharmacokinetic pharmacodynamic relationship; Solid tumor; Treatment resistance; Pharmacodynamics; Enzyme; Transferases; Patient; Malignant tumor; Biological activity; Cyclin dependent kinase inhibitor; Pharmacokinetics; Cyclin dependent kinase; Cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdq734

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