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• W2244860544 abstract "e13026 Background: MK-5108 is a potent, highly selective Aurora A kinase inhibitor. Aurora A is a serine/threonine kinase that plays a critical role in mitotic spindle formation and centrosome maturation. Preclinical studies of MK-5108 have demonstrated robust sensitization of tumor cells to taxanes, induction of biomarkers of Aurora A inhibition, and efficacy in rat xenograft models as monotherapy and in combination with taxanes. Methods: Objectives of this multicenter first in human study were to evaluate 1) the safety and tolerability profile, 2) PK, 3) PD effects, and 4) antitumor activity of MK-5108 as monotherapy (MT - Panel 1) and in combination (CT - Panel 2) with docetaxel. MT patients receive oral MK-5108 q 12 hr for 2 days every 14-21 days. CT patients receive docetaxel IV at 60 mg/m2 followed by oral MK-5108 q 12 hr for 2 days every 21 days. A 3+3 dose escalation scheme of MK-5108 is employed with a fixed dose of docetaxel. MK-5108 PK and pre- and post- skin and hair follicle biopsies for PD markers are obtained in Cycle 1. Results: 34 patients have been treated with MK-5108; 17 patients in Panel 1 (MT) with doses ranging from 200 to 1800 mg q 12 hr and 17 patients in Panel 2 (CT) with doses ranging from 100-225 mg q 12 hr. No DLTs were identified in Panel 1 and an MTD has not been established in MT. CT patients experienced a DLT of febrile neutropenia (3). Other Gr 3/4 AEs in CT included neutropenia, leucopenia, lymphopenia, sinus bradycardia (1), and angioedema (1). Plasma AUC0-12hr and Cmax appeared to increase dose proportionally following the 1st dose but less than dose proportionally following the 4th dose. The apparent terminal half-life ranged from 8.3 to 13.5 hrs. All patients reached a 2 μM preclinical target efficacious concentration following the 4th 1200-mg dose. Stable disease was observed in 7 patients in MT, 4 in CT, and partial response (2) was noted in CT. Conclusions: MK-5108 is well tolerated in MT at doses up to 1,800 mg q 12 hours for 2 days every 14-21 days at plasma levels reaching the preclinical target. MT will now enroll to obtain pre- and post-tumor biopsies to examine with PD markers. Preliminary results suggest that MK-5108 may have clinical activity even when used as a single agent. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, sanofi-aventis Bayer, Enzon, Genentech, ImClone Systems, Lilly, Merck, Novartis, Pfizer, PhytoCeutica, Roche, sanofi-aventis, Taiho Pharmaceutical, Taxolog, Wyeth" @default.
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• W2244860544 date "2010-05-20" @default.
• W2244860544 modified "2023-09-27" @default.
• W2244860544 title "A phase I study of MK-5108, an oral aurora A kinase inhibitor, in both monotherapy and in combination with docetaxel in patients with advanced solid tumors." @default.
• W2244860544 doi "https://doi.org/10.1200/jco.2010.28.15_suppl.e13026" @default.
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