Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors.
OBJECTIVE
To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of the 24-h continuous intravenous (CIV) infusion of MK-0457, a novel pan-Aurora kinase inhibitor, in patients with advanced solid tumors and to determine the bioavailability of an oral dose of 100 mg MK-0457.


METHODS
MK-0457 was administered as a 24-h CIV infusion every 21 days. Dose escalation proceeded per toxicity criteria. A 100-mg oral dose was administered to seven patients 48 h prior to the CIV infusion dose of 64 mg/m(2)/h.


RESULTS
Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m(2)/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m(2)/h. The most common adverse events were nausea, vomiting, diarrhea, and fatigue. Pharmacokinetic analyses revealed that CIV infusion MK-0457 had an estimated mean terminal half-life of approximately 6.6-10.2 h and that end-of-infusion concentrations and mean AUCs were approximately dose proportional. The estimated mean oral bioavailability of MK-0457 was 7.9%. One patient with advanced ovarian cancer attained prolonged stable disease for 11 months.


CONCLUSIONS
MK-0457 was well tolerated in this schedule. Almost half the patients attained stable disease. Further development of this class of agents will likely occur in combination with other anti-cancer treatments.
Traynor
Anne M
AM
University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, 3103 WIMR, 1111 Highland Avenue, Madison, WI 53705, USA. amt@medicine.wisc.edu
Hewitt
Maureen
M
Liu
Glenn
G
Flaherty
Keith T
KT
Clark
Jason
J
Freedman
Steven J
SJ
Scott
Boyd B
BB
Leighton
Ann Marie
AM
Watson
Patricia A
PA
Zhao
Baiteng
B
O'Dwyer
Peter J
PJ
Wilding
George
G
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D064127:Aurora Kinases; D001682:Biological Availability; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064127:Aurora Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
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