A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.

Abstract

BACKGROUND:

AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks.

METHODS:

Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients.

RESULTS:

Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment.

CONCLUSIONS:

AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.

• Authors: E X Chen, S Hotte, H Hirte, L L Siu, J Lyons, M Squires, S Lovell, S Turner, L McIntosh, L Seymour
• Journal: British journal of cancer (Br J Cancer) Vol. 111 Issue 12 Pg. 2262-7 (Dec 09 2014) ISSN: 1532-1827 [Electronic] England
• PMID: 25393368 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide
• Piperidines
• Protein Kinase Inhibitors
• Pyrazoles
• Cyclin-Dependent Kinases

Topics

• Adult
• Aged
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, enzymology, metabolism)
• Piperidines (administration & dosage, adverse effects, pharmacokinetics)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrazoles (administration & dosage, adverse effects, pharmacokinetics)