A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies.
BACKGROUND
AT9283 is an inhibitor of aurora kinases A and B with antitumor activity in preclinical models. This a First in Human phase I study assessed the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of AT9283.


METHODS
Patients with advanced tumors received AT9283 as a continuous central venous infusion over 3 days in cohorts of three to six patients starting at 1.5 mg/m(2)/day (equivalent to 4.5 mg/m(2)/72 h). The oral bioavailability of AT9283 was assessed in a cohort of seven patients. Pharmacodynamic analysis of biomarkers included phosphorylation of histone H3 on serine 10, proliferating cell nuclear antigen, Ki67, M30 and M65 in skin and plasma.


RESULTS
Forty patients were included in all analyses. AT9283 was generally well tolerated with main toxic effects of reversible dose-related myelosuppression, gastrointestinal disturbance, fatigue and alopecia. The dose-limiting toxicity of AT9283 was grade 3 febrile neutropenia in two patients at 36 mg/m(2)/72 h and the maximum tolerated dose (MTD) was established at 27 mg/m(2)/72 h. Systemic exposure was dose proportional. The mean oral bioavailability of a 0.9 mg/m(2) dose was 29.4% (range 11.2%-36.7%). Pharmacodynamic analyses indicated antiproliferative and apoptotic activity of AT9283. Four patients with esophageal, non-small-cell lung cancer (n = 2) and colorectal cancer demonstrated RECIST stable disease ≥ 6 months.


CONCLUSIONS
AT9283 was well tolerated up to the MTD of 27 mg/m(2)/72 h. AT9283 is currently assessed in phase II trials.
Drug Development Unit, Royal Marsden NHS Foundation Trust, Surrey, London.
H-T
HT
Arkenau
Northern Centre for Cancer Treatment, Newcastle upon Tyne.
R
R
Plummer
Drug Development Unit, Royal Marsden NHS Foundation Trust, Surrey, London.
L R
LR
Molife
Drug Development Unit, Royal Marsden NHS Foundation Trust, Surrey, London.
D
D
Olmos
Drug Development Unit, Royal Marsden NHS Foundation Trust, Surrey, London.
T A
TA
Yap
Astex Therapeutics Ltd, Cambridge, UK.
M
M
Squires
Astex Therapeutics Ltd, Cambridge, UK.
S
S
Lewis
Astex Therapeutics Ltd, Cambridge, UK.
V
V
Lock
Astex Therapeutics Ltd, Cambridge, UK.
M
M
Yule
Astex Therapeutics Ltd, Cambridge, UK.
J
J
Lyons
Northern Centre for Cancer Treatment, Newcastle upon Tyne.
H
H
Calvert
Drug Development Unit, Royal Marsden NHS Foundation Trust, Surrey, London. Electronic address: ian.judson@icr.ac.uk.
I
I
Judson
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D064127:Aurora Kinases; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D015331:Cohort Studies; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
C535237:1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D014508:Urea; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases