A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.
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.
Princess Margaret Cancer Centre, University Health Network, Room 5-719, 610 University Avenue, Toronto, Ontario, Canada.
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EX
Chen
Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada.
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Hotte
Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada.
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Hirte
Princess Margaret Cancer Centre, University Health Network, Room 5-719, 610 University Avenue, Toronto, Ontario, Canada.
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Siu
Astex Pharmaceutics, Cambridge, UK.
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Lyons
Astex Pharmaceutics, Cambridge, UK.
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Squires
Princess Margaret Cancer Centre, University Health Network, Room 5-719, 610 University Avenue, Toronto, Ontario, Canada.
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Lovell
Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada.
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Turner
NCIC Clinical Trials Group, Kingston, Ontario, Canada.
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McIntosh
NCIC Clinical Trials Group, Kingston, Ontario, Canada.
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Seymour
D000328:Adult; D000368:Aged; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
C531230:4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D018844:Cyclin-Dependent Kinases