Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors
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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.
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/m2/h.
Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m2/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m2/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.
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.
KeywordsPhase I Aurora kinase Serine/threonine protein kinases BCR-ABL mutations
- 17.Cervantes-Ruiperez A, Elez ME, Rosello T, Macarulla T, Rodriguez-Braun E, Lee Y et al (2009) Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MLN8237, a novel selective aurora A kinase (AAK) inhibitor, in patients (pts) with advanced solid tumors. J Clin Oncol 27:124 sGoogle Scholar
- 18.Robert F, Verschraegen C, Hurwitz H, Uronis H, Advani R, Chen A et al (2009) A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid tumor patients. J Clin Oncol 27:117 sGoogle Scholar
- 19.Jones SF, Burris HA, Dumez H, Infante JR, Fowst C, Gerletti P et al (2008) Phase I accelerated dose-escalation, pharmacokinetic (PK) and pharmacodynamic study of PF-03814735, an oral aurora kinase inhibitor, in patients with advanced solid tumors: Preliminary results. J Clin Oncol 26:116 sGoogle Scholar
- 20.Foran JM, Ravandi F, O’Brien SM, Borthakur G, Rios M, Boone P et al (2008) Phase I and pharmacodynamic trial of AT9283, an aurora kinase inhibitor, in patients with refractory leukemia. J Clin Oncol 26:116 sGoogle Scholar
- 21.Cohen RB, Jones SF, von Mehren M, Cheng J, Spiegel DM, Laffranchi B et al (2008) Phase I study of the pan aurora kinases (AKs) inhibitor PHA-739358 administered as a 24 h infusion without/with G-CSF in a 14-day cycle in patients with advanced solid tumors. J Clin Oncol 26:117 sGoogle Scholar
- 22.Rubin EH, Shapiro GI, Stein MN, Watson P, Bergstrom D, Xiao A et al (2006) A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457 in cancer patients. J Clin Oncol 24:123 sGoogle Scholar
- 28.Papayannidis C, Iacobucci I, Soverini S, Paolini S, Cilloni D, Messa F et al (2009) Innovative phase I study of concomitant and consecutive treatment with dasatinib and MK-0457 in refractory Ph + CML and ALL patients. J Clin Oncol 27:375 sGoogle Scholar