Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors.
OBJECTIVE
Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments.


METHODS
Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m(2) in the 6-hour IVS, and from 250 mg/m(2) in the 3-hour IVS, were studied.


RESULTS
Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m(2) for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m(2) or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients.


CONCLUSIONS
Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m(2) infused over 6 hours on days 1, 8, and 15 every 28 days.
Steeghs
Neeltje
N
Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
Eskens
Ferry A L M
FA
Gelderblom
Hans
H
Verweij
Jaap
J
Nortier
Johan W R
JW
Ouwerkerk
Jan
J
van Noort
Conny
C
Mariani
Mariangela
M
Spinelli
Riccardo
R
Carpinelli
Patrizia
P
Laffranchi
Bernard
B
de Jonge
Maja J A
MJ
D000328:Adult; D000368:Aged; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C523797:danusertib