A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors
Background: MK-5108 is really a potent/highly selective Aurora A kinase inhibitor.
Methods: A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT Panel1/n = 18 200 to 1800 mg) or perhaps in combination (CT Panel2/n = 17 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the utmost tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This research was ended early because of toxicities in Panel2 at MK-5108 doses underneath the anticipated PK exposure target.
Results: 35 patients enrolled (33 evaluable for tumor response). No dose-restricting toxicities (DLTs) were noticed in Panel1 three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, correspondingly G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax elevated under dose proportionally following a first MT dose but elevated roughly dose proportionally across 200 to 3600 mg/next day of fourth dose. The t1/2 ranged from 6.6 to 13.5 h across both MK-5108 panels. No obvious effects on immunohistochemistry markers were observed however, significant dose-related increases in gene expression were seen pre-/publish-treatment. Best responses were 9/17 stable disease (SD) (Panel1) in addition to 1/16 PR and sevenOr16 SD (Panel2) (450 mg/day).
Conclusions: MK-5108 MT was well tolerated at doses as much as 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 µM*hr). The MTD for MK-5108 docetaxel (CT) started at 300 mg/day, underneath the exposure target. Utilization of pharmacodynamic gene expression assays to find out target engagement was validated.